Acamprosate formulations, methods of using the same, and combinations comprising the same

ABSTRACT

Embodiments disclosed herein generally relate to acamprosate formulations, methods of use of the formulations, to methods of using the formulations in combination with at least one other medication, and to combination products and compositions comprising the formulations and at least one other medication, such as neuroleptic (antipsychotic) and/or antidepressant drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/853,876, filed on Mar. 29, 2013, entitled “ACAMPROSATE FORMULATIONS,METHODS OF USING THE SAME, AND COMBINATIONS COMPRISING THE SAME,” whichis a continuation of U.S. application Ser. No. 13/745,619, filed on Jan.18, 2013, entitled “ACAMPROSATE FORMULATIONS, METHODS OF USING THE SAME,AND COMBINATIONS COMPRISING THE SAME,” which is a continuation in partof PCT Application No. PCT/US2012/067507, filed on Dec. 2, 2012,entitled “ACAMPROSATE FORMULATIONS, METHODS OF USING THE SAME, ANDCOMBINATIONS COMPRISING THE SAME,” which claimed the benefit of priorityunder 35 U.S.C §119(e) of U.S. Provisional Application No. 61/566,550filed on Dec. 2, 2011, and U.S. Provisional Application No. 61/649,137,filed on May 18, 2012, both entitled “METHODS OF USING ACAMPROSATEFORMULATIONS AND COMPOSITIONS COMBINING ACAMPROSATE FORMULATIONS WITHNEUROLEPTIC DRUGS,” each of which is hereby incorporated herein byreference in its entirety and is to be considered a part of thisspecification.

BACKGROUND

1. Field

Embodiments disclosed herein generally relate to methods of use ofimproved formulations of acamprosate (calcium N-acetylhomotaurinate) andto compositions and use of compositions comprising medications, such asneuroleptic (antipsychotic) and/or antidepressant drugs, combined withimproved formulations of acamprosate.

2. Description of the Related Art

Acamprosate (calcium N-acetylhomotaurinate) is the calcium salt of aderivative of the amino acid taurine. It is known to facilitate GABA-Aneurotransmission and to modulate neuronal responses to the stimulationof both NMDA-type glutamate receptors and certain classes ofmetabotropic glutamate receptors. In particular, it reduces the responseof the voltage-operated calcium channel to high levels of stimulation byglutamate. (Wilde & Wagstaff, Drugs 53:1039-53, 1997). Acamprosate isused clinically in the treatment of abstinent alcoholics to reduce orinhibit the craving for alcohol. Several U.S. patents (e.g., U.S. Pat.Nos. 6,057,373, 6,294,583, 6,391,922, 6,689,816, and 7,498,361; each ofwhich is incorporated herein by reference in its entirety) describe theuse of acamprosate to treat neuropsychiatric disorders, includingtardive dyskinesia and other movement disorders induced by chronicexposure of patients to neuroleptic (antipsychotic) drugs, Tourette'ssyndrome, and mental disorders such as posttraumatic stress disorder(PTSD) and obsessive-compulsive disorder (OCD).

SUMMARY

Acamprosate is a compound with high solubility and lowpermeability—Class III under the Biopharmaceuticals ClassificationSystem (BCS). The bioavailability of BCS Class III compounds tends to below because the absorption of such compounds occurs either viadiffusion—which is slow and inefficient because of the lowpermeability—or via specialized transporters in the membranes ofintestinal mucosal cells—which may not exist, may poorly bind thecompound, or may be easily saturated, implying zero-order kinetics.

Some embodiments herein are related to methods and compositions wherethe pharmacokinetics (PK) of acamprosate are altered. The PK ofacamprosate can be altered, for example, when the acamprosate isformulated for controlled release by gastroretentive (GR) deliverysystems—solid state dosage forms that are retained in the stomach forseveral hours, during which time the formulations gradually release theacamprosate into the gastric milieu.

There are several different methods for creating GR delivery systems;they have been described in review articles (not an exhaustive orlimiting list) over the past several years, e.g., Pharmainfo.net, Volume6, Issue 1, Feb. 3, 2008; Garg S and Sharma S, Gastroretentive DrugDelivery System, Business Briefing, Pharmatech 2003, Nayak A K, Maji R,Das B, Gastroretentive Drug Delivery Systems, a Review, Asian Journal ofPharmaceutical and Clinical Research, Volume 3, Number 1, January-March2010, pp 1-10; each of which is incorporated herein by reference in itsentirety. These systems all can be applied to acamprosate. Their effectis to deliver the drug to the proximal duodenum at a controlled rate,usually over several hours.

Some embodiments described herein are based upon the discovery ofbenefits associated with formulating acamprosate utilizing technology,such as GR formulation technology. Without being limited thereto, twopractical benefits of the altered PK discovered when using suchformulations are efficacy with less frequent dosing and avoidance ofdose-dependent side effects related to the C_(max), which is lower withGR formulations than with immediate-release (IR) formulations containingthe same amount of acamprosate. An additional non-limiting benefit isthe potential efficacy of a lower total oral dose of the drug for itsclinical indication. Furthermore, even in embodiments where the GRsystem does not offer greater bioavailability—i.e., a larger area underthe time-concentration curve (AUC) for a given oral dose—it can increasethe efficacy of an oral dose by increasing the target site residencetime at which the concentration exceeds a minimal threshold forefficacy.

Embodiments described herein generally relate to the use of improvedformulations of acamprosate and other salts of N-acetylhomotaurine orother related compounds. Some particular embodiments relate toformulations based on gastric-retentive (GR) delivery systems. Someembodiments relate to the use of improved formulations of acamprosate totreat neuropsychiatric disorders including tardive dyskinesia usingdosages and dosage schedules not heretofore known to be efficacious.These dosages and dosage schedules can provide greater convenience andgreater tolerability of treatment, and thus greater effectiveness oftreatment because of better treatment adherence and tolerability ofdosages sufficient for more complete relief of symptoms.

In some aspects, the improved formulations can be used to treatconditions, such as those listed above and elsewhere herein, with totaldaily dosages of acamprosate of less than 1 gram, given on a once-dailyor twice-daily schedule, for example. This contrasts withheretofore-described therapeutic use of the currently-marketedenteric-coated acamprosate tablets. These must be given in doses of 2grams or more per day to be efficacious in treating alcoholism, usuallyon a three times daily schedule and many patients require 2 grams ormore to get relief of symptoms.

The efficacy of the lower doses is not necessarily based on the improvedformulations being bioequivalent to higher doses of thecurrently-marketed enteric coated preparation. In fact the total AUCproduced by the lower doses of the new formulations may be, in someembodiments, equal to or significantly lower than those produced withusual doses of the currently-marketed formulations, and in someembodiments the C_(max) produced by the new formulations can be lowerthan that produced with the currently marketed formulation at a dosewith equal efficacy.

Some embodiments also concern compositions and use of fixed-dosecombinations of improved formulations of acamprosate withfirst-generation neuroleptic (antipsychotic) drugs, second generationneuroleptic drugs, selective serotonin reuptake inhibitors (SSRIs),serotonin norepinephrine reuptake inhibitors (SNRIs), or the anti-nauseadrug metoclopramide. For example, the decreased dosage amount andfrequency of dosing made possible by the improved formulations makes itfeasible to formulate fixed-dose combinations of acamprosate and othermedications, such as first-generation neuroleptic drugs. The fixed dosecombinations with neuroleptics, for example, can provide effectivetreatment of psychosis with a lesser risk of metabolic side effects thanseen with second-generation neuroleptic drugs, a lesser risk of tardivedyskinesia than seen with first and second generation neuroleptic drugsgiven alone, and with, unexpectedly, increased relief of mental symptomscompared with first-generation neuroleptic drugs given alone.

Some embodiments relate to combinations of from 100 mg to less than 1gram (e.g., 800 mg) of acamprosate with a drug from a second class, forexample, where the second drug is given in a dose ranging from half ofthe lower end of its usual dosage range to the upper end of its dosagerange. The combination pill may be given either once or twice a day totreat a neuropsychiatric disorder, for example.

As noted, some embodiments relate to combinations of acamprosatecombined with a second medication, such as for example, a neurolepticmedication. The fixed dose compositions comprising a first or secondgeneration neuroleptic combined with an improved formulation ofacamprosate can be used to treat any of the disorders treated with, forexample, neuroleptic drugs or metoclopramide, including schizophrenia,schizoaffective disorder, bipolar disorder, major depression, delusionaldisorder, organic psychoses, delirious agitation, or nausea andvomiting. They can be given for this purpose on a once-daily ortwice-daily schedule (or more if desired), typically with a single pillgiven each time. They can provide for a given dosage of neuroleptic,equal or greater benefit for the neuropsychiatric disorder or symptomsbeing treated, and can offer greater relief of anxiety and agitationwhen these are among the symptoms. Compared with the same dose of afirst-generation neuroleptic given without acamprosate, thesecombinations entail a lower risk of tardive dyskinesia and other tardivemovement disorders, and they cause movement disorder of lesser severity,if they cause one at all. In contrast with second-generationneuroleptics of equal therapeutic efficacy, these combinations can carrya lesser risk of significant metabolic disturbances including weightgain, glucose intolerance, and increased risk of atheroscleroticcardiovascular disease.

In the case of acamprosate combined with a neuroleptic, the combinationcan reduce the risk of tardive dyskinesia (TD) associated with givingthe neuroleptic drug. Also, unexpectedly, the combination has additionalbenefits for the patient's mental status, such as decreased anxietyand/or agitation (as shown in the patient example). If the patient haspre-existing TD associated with cognitive impairment the acamprosate mayalso have, as claimed in prior patents, improvement in cognition. Theaction of acamprosate to treat—and consequentially to prevent themanifestation of—tardive dyskinesia, combined with the additionalbenefit of improving some mental symptoms—makes higher-potency andfirst-generation neuroleptic drugs more attractive when they are givenin combination with acamprosate. At present the first-generation,high-potency neuroleptic drugs are avoided because they are more likelythan second-generation neuroleptic drugs to produce tardive dyskinesia.However, those drugs are no less efficacious in treating psychosis thanthe second-generation drugs (with the sole exception of clozapine),which usually are more expensive, and which have serious metaboliceffects with potentially life-threatening consequences. It is rationalto combine even second-generation neuroleptics with acamprosate, becausethose drugs still carry some risk of TD, and the additional psychiatricbenefit can still apply. Tables 10 and 11 below show non-limitingexamples of the dose ranges for the neuroleptic drugs and the GRacamprosate formulation to be used in fixed dose combinations.

Some embodiments relate to compositions or methods of using compositionswhere the compositions further include a substance to induce a fed statein a patient. For example, the compositions can include alpha-lipoicacid, either as racemic alpha-lipoic acid or as R enantiomer ofalpha-lipoic acid. In some aspects of the above uses, compositions ormethods, the alpha-lipoic acid can be in a dosage of from about 40 to600 mg or any value or sub range there between. In some aspects, thealpha-lipoic acid can be in a dosage of from about 100 to about 300 mg,or any value or sub range there between. In some aspects, thealpha-lipoic acid can be at least part of a gastric-retentivecomposition. In some aspects, the alpha-lipoic acid can at leastpartially be in the coating of the gastric-retentive system. In someaspects, the alpha-lipoic acid can be incorporated into agastric-retentive system. In some aspects, the gastric-retentive systemmay be designed to release the alpha-lipoic acid within a period of timeafter ingestion, for example, the first hour after ingestion. In someaspects, alpha-lipoic acid may be included in a formulation or dosageform that also includes acamprosate, where the acamprosate is in a dose,for example, of 100 to less than 1 gram (e.g., 800-900 mg), or any valueor sub range there between. In some aspects, alpha-lipoic acid may beincluded in a formulation or dosage form that includes acamprosate andthat further includes a second medication, for example, a neuroleptic(antipsychotic) drug.

Also presented herein is a composition comprising acamprosate in a doseof about 100 to less than 1 gram (e.g., 100-700 mg or 100-900 mg; or anyvalue or sub range there between) and alpha-lipoic acid in a dosage ofabout 100 to about 600 mg (or any value or sub range there between).

Also presented herein is a composition comprising alpha-lipoic acid in adosage of about 100 to about 300 mg in a gastric-retentive compositioncomprising acamprosate and another medication (e.g., a neuroleptic(antipsychotic) drug), for example, as active pharmaceuticalingredients.

Some embodiments relate to methods of treating a neuropsychiatricdisorder, which methods can include for example, administering to apatient in need thereof a total daily dosage of acamprosate of less than1000 mg, wherein the acamprosate is administered once or twice daily toachieve the total daily dosage, and the administered acamprosate is in acomposition that is formulated to release at least 50% of theacamprosate within the stomach of the recipient at a controlled rateover a 4-8 hour period.

In some aspects the composition can be formulated to release from about50% to 99% of the acamprosate in the stomach. The composition mayinclude for example, one or more gastric retentive excipients, one ormore controlled release excipients, or one or more gastric retentiveexcipients and one or more controlled release excipients. The one ormore gastric retentive excipients can be, for example, a floatingexcipient that is non-effervescent, a floating excipient that iseffervescent, a bioadhesive excipient, a mucoadhesive excipient, anexcipient that swells, an excipient that expands, a magnetic excipient,and the like. The one or more controlled release excipients can include,for example, a technology that forms a matrix, forms a coated bead, isosmotic or acts by ion exchange. The administered composition may beformulated to achieve a mean AUC for acamprosate that is greater thanthe mean AUC for an immediate release composition of a acamprosate, tohave a C_(max) for acamprosate that is less than the C_(max) for animmediate release composition, and/or to have a T_(max) for acamprosatethat is delayed compared to the T_(max) for an immediate releasecomposition.

The composition may include, for example, one or more polymers thatpromote retention in the stomach of the recipient, for example, one ormore of CARBOPOL® 974P (carbomer homopolymer type B) andcarboxymethylcellulose. The polymers may be present in any suitableamount or range, for example, in some non-limiting embodiments fromabout 3% to 70% or any range or value within that broader range. Forexample, one or more hydrophilic polymers can be present in an amount ofabout 5% to about 20%.

The acamprosate can be administered once daily or twice daily forexample. The administered once or twice daily acamprosate respectivelycan be a dosage of less than 1 gram, for example, in a dosage of 200 mgto 450 mg or 350 mg to 900 mg. Without being limited thereto, whenadministered the acamprosate can be administered as one or two units ofa dosage form, for example, one or two pills, tablets or capsules. Thesingle unit of a dosage form or the multiple units of a dosage form canhave, for example, a total weight of less than 1200 mg. For example, insome embodiments herein, the total unit dosage form wait can be between400 and 1200 mg, between 500 and 1200 mg, between 600 and 1200 mg, orany value or sub range within those ranges.

The methods further can include administering the acamprosate to apatient in a fed state or can include inducing a fed state in thepatient. The neuropsychiatric disorder can be for example, tardivedyskinesia and other movement disorders induced by chronic exposure ofpatients to neuroleptic (antipsychotic) drugs, Tourette syndrome,posttraumatic stress disorder (PTSD) obsessive-compulsive disorder(OCD), and the like.

Some embodiments relate to improved methods of treating tardivedyskinesia with acamprosate, the improvement comprising providing anacamprosate dosage form once or twice per day wherein the dosage formcomprises less than 1 gram of acamprosate, for example, from 50 to 900mg of acamprosate (more preferably 50-500 mg), which dosage form uponadministration releases acamprosate into the stomach of a patient at acontrolled rate over a period from 3 to 10 hours, wherein the totaldaily dose of acamprosate provided is less than 1000 mg. In some aspectsat least 50% of the acamprosate is released into the stomach within atleast 3-4 hours.

Some embodiments relate to compositions that include acamprosate in adosage of less than 1 gram or less than 900 mg that is formulated toretain the composition in the stomach of the recipient and to controlthe release of the acamprosate for a period of time sufficient torelease at least 50% of the acamprosate from the composition into thestomach within a 4 hour period and to release acamprosate at acontrolled rate over a period of 4 to 8 hours, wherein at least 90% ofthe acamprosate is released from the composition within 8 hours.

The composition can include for example, a gastric retentive technology,a controlled release technology, or both a gastric retentive and acontrolled release technology. The one or more gastric retentiveexcipients are selected from the group consisting of a floatingexcipient that is non-effervescent, a floating excipient that iseffervescent, a bioadhesive excipient, a mucoadhesive excipient, anexcipient that swells, an excipient that expands, a magnetic excipient,and the like. The one or more controlled release excipients can include,for example, a technology that forms a matrix, that forms a coated bead,that is osmotic, that acts by ion exchange, or the like. The compositionmay include, for example, one or more polymers, such as one or more ofCARBOPOL® 974P (carbomer homopolymer type B) and carboxymethylcellulose,and the like. The composition can be formulated such that uponadministration to a recipient the mean AUC for acamprosate is equal toor greater than the mean AUC For an immediate release composition of aacamprosate, the C_(max) for acamprosate is less than the C_(max) for animmediate release composition, and/or the T_(max) for acamprosate islonger than for immediate release acamprosate.

The acamprosate dosage can be, for example, between less than 1 gram(e.g., 100 mg and 800 mg) or any value or range within that range. Thecomposition can be formulated, for example, as a tablet, a pill, acapsule, or the like. The composition further may include, for example,alpha lipoic acid, where the alpha lipoic acid is either racemic alphalipoic acid or the R-enantiomer of alpha-lipoic acid, and the dosage ofalpha lipoic acid is between 50 mg and 600 mg.

Some embodiments relate to methods of treating a neuropsychiatricdisorder by administering to a patient in need thereof a composition asset forth above or elsewhere herein, wherein the total daily dosage ofacamprosate administered is less than 1000 mg, wherein the compositionis administered once or twice daily to achieve the total daily dosage.

Some embodiments relate to combination products that include, forexample, a composition as described above and elsewhere herein and atleast a second medication that includes one or more of an antipsychotic(neuroleptic) medication, a selective serotonin reuptake inhibitor(SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), anantidepressant, an anti-anxiety medication, or the like. Theantipsychotic medication can be, for example, a first or a secondgeneration antipsychotic. The first or a second generation antipsychoticcan be for example, one or more of thioridazine, chlorpromazine,thiothixene, trifluoperazine, fluphenazine, haloperidol, perphenazine,loxapine, molindone, metoclopramide, aripiprazole, asenapine,iloperidone, lurasidone, olanzapine, paliperidone, quetiapine,risperidone, ziprasidone, and the like. The SSRI or SNRI can be, forexample, one or more of citalopram, desvenlafaxine, duloxetine,escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,sertraline, venlafaxine, and the like. The product may include, forexample, a single dosage form unit that includes, consists or consistsessentially of both acamprosate and at least one second medication.

Some embodiments relate to methods of treating a neuropsychiatricdisorder, for example, by administering to a patient in need thereof acombination product as described above, and elsewhere herein, whereinthe total daily dosage of acamprosate administered is less than 1000 mg,wherein the composition is administered once or twice daily to achievethe total daily dosage. The product can be or may include, for example,a pill, a tablet, a capsule or the like comprising acamprosate and atleast one second medication. Still some embodiments relate to methods ofreducing the risk or delaying the onset of tardive dyskinesia comprisingadministering to a patient in need thereof a combination product asdescribed herein, wherein the total daily dosage of acamprosateadministered is less than 1000 mg, wherein the composition isadministered once or twice daily to achieve the total daily dosage. Theproduct can be or may include, for example, a pill, a tablet, a capsuleor the like comprising acamprosate and at least one second medication.

Also, some embodiments relate to methods of or uses of acamprosate forimproving compliance with an acamprosate treatment regimen. The methodscan include for example, providing to a patient a total daily dosage ofacamprosate of less than 1 gram (e.g., 900 mg) and administering aneffective amount of an acamprosate formulation once or twice daily,which formulation is formulated to release at least 50% of theacamprosate within the stomach of the recipient at a controlled rateover a 4-8 hour period. In some aspects, at least 50% is released withinthe first 4 hours. In some aspects, at least 90% is released from thecomposition within 8 hours. In some aspects, the patient can be apatient is selected, identified or by virtue of having been at leastpartially non-compliant with a previous treatment regimen. The treatmentregimen can include, for example, alcoholism, treatment of a movementdisorder, treatment of anxiety, treatment of depression, and the like.

Some embodiments relate to methods of or uses of acamprosate forreducing anxiety in a patient receiving a neuroleptic, anxiety orantidepressant medication. The methods can include for example,providing to a patient a total daily dosage of acamprosate of less than1 gram (e.g., 900 mg) and administering an effective amount of anacamprosate formulation once or twice daily, which formulation isformulated to release at least 50% of the acamprosate within the stomachof the recipient at a controlled rate over a 4-8 hour period. In someaspects, at least 50% is released within the first 4 hours. In someaspects, at least 90% is released from the composition within 8 hours.The methods further can include, for example, identifying a patientsuffering from anxiety despite receiving one of said medications or apatient in need of at least some reduction in anxiety despite receivingone of said medications.

Some embodiments relate to methods for or uses of acamprosate forreducing acamprosate side effects associated with treatment with dosagesof greater than 1 gram. The methods can include, for example,administering to a patient in need thereof a total daily dosage ofacamprosate of less than 1000 mg, wherein the acamprosate isadministered once or twice daily to achieve the total daily dosage, andthe administered acamprosate is in a composition that is formulated torelease at least 50% of the acamprosate within the stomach of therecipient at a controlled rate over a 4-8 hour period. In some aspects,at least 50% is released within the first 4 hours. In some aspects, atleast 90% is released from the composition within 8 hours. The sideeffect can be, for example, nausea and/or vomiting.

Some embodiments relate to methods of or uses of acamprosate fortreating alcohol dependence comprising administering to a patient inneed thereof a total daily dosage of acamprosate of less than 1000 mg,wherein the acamprosate is administered once or twice daily to achievethe total daily dosage, and the administered acamprosate is in acomposition that is formulated to release at least 50% of theacamprosate within the stomach of the recipient at a controlled rateover a 4-8 hour period. In some aspects, at least 50% is released withinthe first 4 hours. In some aspects, at least 90% is released from thecomposition within 8 hours.

A method of treating alcohol dependence, comprising administering aneffective amount of a pharmaceutical formulation comprising acamprosateto a patient in need thereof, wherein the formulation is formulated withone or more gastroretentive technologies and one or more controlledrelease technologies, which one or more gastroretentive technologies isselected from the group consisting of floating—non-effervescent,floating—effervescent, bioadhesive, mucoadhesive, swelling, expanding,and magnetic and which one or more controlled release technologies isselected from the group consisting of matrix, coated beads, osmotic, andion exchange. In some aspects, the methods of treating alcoholism caninclude GR acamprosate plus alpha lipoic acid; the combination pillbeing taken either in the fed state or in the fasting state.

Furthermore, some embodiments relate to methods of or uses ofacamprosate for treating a neuropsychiatric disorder, comprisingadministering once or twice daily a composition comprising acamprosatein a composition that releases at least 50% of the acamprosate at acontrolled rate over a 4-8 hour period, and wherein the total dailydosage of acamprosate is less than 1000 mg. In some aspects, at least50% is released within the first 4 hours. In some aspects, at least 90%is released from the composition within 8 hours.

Some embodiments relate to uses of acamprosate in the treatment of aneuropsychiatric disorder, wherein the acamprosate is administered onceor twice daily as part of a composition comprising the acamprosate,wherein the composition releases at least 50% of the acamprosate at acontrolled rate over a 4-8 hour period, and wherein the total dailydosage of acamprosate is less than 1000 mg. In some aspects, at least50% is released within the first 4 hours. In some aspects, at least 90%is released from the composition within 8 hours. The disorder can be,for example, schizophrenia, schizoaffective disorder, bipolar disorder,major depressive disorder, delusional disorder, organic psychoses,Tourette Syndrome, and the like. Some embodiments relate to uses ofacamprosate in the treatment of a neuropsychiatric disorder, wherein theacamprosate is formulated for once or twice daily administration in acomposition that releases the acamprosate at a controlled rate over a4-8 hour period, and wherein the total daily dosage of acamprosate isless than 1000 mg. In some aspects, at least 50% is released within thefirst 4 hours. In some aspects, at least 90% is released from thecomposition within 8 hours.

Some embodiments relate to compositions that include for example, afixed dose of acamprosate in a gastroretentive controlled-releaseformulation where the dose of acamprosate is less than 1 gram (e.g.,between 50 and 900 mg). Also, some embodiments relate to compositionsthat include a fixed dose of acamprosate in a gastroretentivecontrolled-release formulation and a fixed dose of a first-generationneuroleptic or a second-generation neuroleptic, a second generationneuroleptic or a fixed dose of metoclopramide, where the dose ofacamprosate is less than 1 gram (e.g., between 50 and 900 mg). Thedosage of the first-generation neuroleptic can be, for example, ½ of itslowest approved dosage up to its highest approved dosage, for example,50% of its lowest approved dosage up to 90% of its lowest approveddosage.

Some embodiments relate to improved method of treating a mental disorderwith a first or second generation neuroleptic, the improvementcomprising administering a composition that comprises acamprosate in anamount of less than 1 gram, for example, 50 to 900 mg (or any value orsub range of less than 1 gram), and a first-generation neuroleptic,wherein the composition is formulated to release at least 50% of theacamprosate into the stomach of the recipient over a 4 to 8 hour period.The mental disorder can be, for example, one or more of schizophrenia,schizoaffective disorder, bipolar disorder, major depressive disorder,delusional disorder, organic psychosis, or Tourette Syndrome.

It should be understood that in the methods, uses and compositionsdescribed herein, that acamprosate can be substitute for by or includedwith any other salt or analog, for example, one more of sodiumN-acetylhomotaurinate, magnesium N-acetylhomotaurinate, or lithiumN-acetylhomotaurinate at the same milligram dose and/or free acidequivalent dose at the same milligram dose.

Still further embodiments relate to the inclusion of a substance toinduce a fed mode in the patient, for example, in order minimize orreduce stomach clearance so as to maintain acamprosate in the stomachfor a longer period of time. The methods, uses, products, formulationsand compositions described herein, further may include, for example,alpha lipoic acid in an amount of 50 mg to 700 mg or any amount or subrange therein (e.g., 100-500 mg.). The alpha lipoic acid can be, forexample, either racemic alpha lipoic acid, an enriched racemic mixturefor one enantiomer or an enantiomer of alpha lipoic acid, such as the Renantiomer. The alpha lipoic acid can be included, for example, at leastpartially in the coating of a formulation. The formulation further caninclude a gastric-retentive system. In some aspects the alpha lipoicacid can be incorporated into a gastric retentive system. For example, agastric retentive systems designed to release the alpha lipoic acidwithin the 30-120 minutes hours after ingestion. The alpha lipoic acidcan be combined with acamprosate in a dosage of 100 to 700 mg (or anyvalue or sub range there between such as 500 mg). Such compositions caninclude the alpha lipoic acid in combination with acamprosate and incombination with a neuroleptic (antipsychotic) drug. In some aspects thealpha-lipoic acid can be in a dosage of 100 to 300 mg in agastric-retentive composition comprising a neuroleptic (antipsychotic)drug and acamprosate as active pharmaceutical ingredients.

The foregoing is a summary and thus contains, by necessity,simplifications, generalization, and omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is not intended to be in any way limiting. Otheraspects, features, and advantages of the devices and/or processes and/orother subject matter described herein will become apparent in theteachings set forth herein. The summary is provided to introduce aselection of concepts in a simplified form that are further describedbelow in the Detailed Description. This summary is not intended toidentify key features or essential features of the claimed subjectmatter, nor is it intended to be used as an aid in determining the scopeof the claimed subject matter.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the pharmacokinetic plot of immediate release versussimulated GR controlled-release acamprosate from a pharmacokinetic study(see EXAMPLE 3 below) conducted in four dogs (beagles). FIG. 1illustrates the results for dog 1 from the study.

FIG. 2 illustrates the results for dog 2 from a pharmacokinetic studyconducted in four dogs, which study is described below in EXAMPLE 3.

FIG. 3 illustrates the results for dog 3 from a pharmacokinetic studyconducted in four dogs, which study is described below in EXAMPLE 3.

FIG. 4 illustrates the results for dog 4 from a pharmacokinetic studyconducted in four dogs, which study is described below in EXAMPLE 3.

DETAILED DESCRIPTION Introduction

Acamprosate (calcium bis acetyl-homotaurine;[3-(acetylamino)-1-propanesulfonic acid] calcium salt), is a derivativeof the amino acid taurine) with effects on both GABA andglutamate-mediated neurotransmission. It is approved in severalcountries for the treatment of alcoholism—specifically, the inhibitionof craving for alcohol in alcohol-dependent patients who are currentlyabstinent. For this purpose acamprosate has limited effectiveness; somecontrolled studies have failed to show efficacy, and adoption of thedrug in practice has not been widespread. Clinical experience, describedin the specification of several issued US patents, has shown acamprosateto be impressively efficacious in the treatment of tardive dyskinesiaand other movement disorders, and in recurrent unwanted stereotypicmovements, behaviors, perceptions, or thoughts, such as those that occurin obsessive-compulsive disorder, tic disorders, Tourette Syndrome,post-traumatic stress disorder, depression, and schizophrenia. Thetherapeutically active moiety in acamprosate is the acetylhomotaurineion; thus, in any of the therapeutic applications of acamprosatedescribed here and elsewhere the drug can be replaced by another salt ofthe same anion, with either a univalent or divalent cation—e.g., sodiumacetylhomotaurinate, lithium acetylhomotaurinate, or magnesiumacetylhomotaurinate. For purposes of the embodiments described herein,acamprosate (or another salt of acetylhomotaurine) can be used alone orin combination to treat various conditions characterized by recurrent,unwanted, stereotypic movements, behaviors, perceptions, or thoughts,including without limitation movement disorders (e.g., hyperkineticmovement disorders such as tardive dyskinesia (“TD”), tardive dystonia,tardive akathisia, peak-dose dyskinesia associated with Parkinson'sdisease treated with levodopa, dystonia, tics, Tourette Syndrome, choreaassociated with Huntington's disease) obsessive-compulsive disorder,posttraumatic stress disorder (PTSD), recurrent intrusive thoughts indepression and stereotypic behavior in schizophrenia and autism.

TD is a chronic disorder of the nervous system, characterized byinvoluntary, irregularly rhythmic movements most often involving themouth, tongue, and facial muscles. Choreatic or dystonic movements ofthe extremities can be involved, as can dystonic movements of the neckor trunk, and rocking movements of the trunk. TD with prominent limbmovements most often is tardive dystonia, a subtype of TD tends to besevere, disabling, and difficult to treat. TD can be accompanied bytardive akathisia, an irresistible impulse to move which is oftenmanifest as continual restless movements of the legs. Another potentialaccompaniment is disruption of respiratory movements leading toirregular breathing and subjective shortness of breath—respiratorydyskinesia. Most cases of TD are caused by long-term use of neuroleptics(antipsychotic drugs); the remainder are caused by chronic use ofdopamine blocking drugs such as metoclopramide or prochlorperazine thatare given to relieve or to prevent nausea and vomiting. However, thereare numerous well-documented cases in which those drugs have induced TDafter only a few weeks of exposure. Unlike many drug side effectstardive dyskinesia can actually get worse when the causative drug isdiscontinued, and the condition can persist for months, years, or evenpermanently afterwards. The prevalence of tardive dyskinesia withlong-term treatment with first-generation antipsychotic drugs is over25%, and even higher in elderly patients.

Second-generation antipsychotic drugs are associated with a lower butstill significant prevalence of tardive dyskinesia—between 1% and 5%depending on the population studied, the specific second-generationneuroleptic given, and the dose of the second-generation neuroleptic.(At higher dosages of some of the second generation neuroleptics, thedopamine receptor blocking action predominates over otherneurotransmitter actions and its pharmacodynamic effect is essentiallythat of a first generation agent.) The second generation drugs, however,have a major problem—they frequently cause weight gain and glucoseintolerance that can lead to frank diabetes and acceleratedatherosclerosis, with significant impact on patients' life expectancy.Thus the second generation neuroleptics do not provide a safealternative to first generation neuroleptics—simply an alternative witha lesser propensity to cause movement disorders. They are not in generalmore efficacious than first generation drugs in the treatment ofschizophrenia, with the sole exception of clozapine, a drug withnumerous other adverse effects including seizures and agranulocytosisthat limit its clinical use.

Acamprosate can be used as a treatment for obsessive compulsive disorder(OCD), posttraumatic stress disorder (PTSD), and other neuropsychiatricconditions characterized by recurrent, involuntary, unwanted, andstereotyped movements, behaviors, thoughts, or perceptions—the symptomsof OCD and PTSD falling within that broader ambit. Serotonin reuptakeinhibitors—both selective serotonin reuptake inhibitors andserotonin-norepinephrine reuptake inhibitors—can have therapeuticbenefits in PTSD and OCD. Thus, some embodiments relate to thecombination of acamprosate and an SSRI or SNRI. The fact that GRacamprosate formulations as described herein can be efficacious in totaldoses of less than 1 gram per day, given on a once-daily or twice-dailybasis, makes such combinations feasible, which they were not heretoforewhen only enteric-coated acamprosate was available and therapeuticefficacy typically required 2 grams per day or more, entailing six ormore enteric-coated tablets per day on a three times daily schedule.

Thus, some embodiments relate to combinations of GR acamprosate witheither an SSRI or an SNRI. Examples of non-limiting amounts or dosagesare provided herein. These combinations can be given once or twicedaily, for example. Also, some embodiments relate to the treatment ofneuropsychiatric conditions characterized by recurrent, involuntary,unwanted and stereotyped movements, behaviors, thoughts, or perceptions,and in particular PTSD and OCD.

Acamprosate when used to treat alcoholism is typically administered in333-mg enteric-coated tablets. The dose is two tablets (666 mg) threetimes daily, for a total dose of approximately two grams. Doses of up to3 grams (three tablets three times a day) have been studied asalcoholism treatment; the higher dose does not appear to be moreeffective and it has more gastrointestinal side effects. One reportedstudy assessed the pharmacokinetics of acamprosate using liquidchromatography (Hammarberg, et al., “Acamprosate Determinations inPlasma and Cerebrospinal Fluid After Multiple Dosing Measured by LiquidChromatography—Mass Spectroscopy: A Pharmacokinetic Study in HealthyVolunteers,” The Drug Monit, 2010, 32:489-496). It showed that bloodlevels of acamprosate build up with repeated dosing, for example, 666 mgdoses. The instant technology that can efficaciously provide sub 1 gramtotal daily doses is surprising and unexpected in view of such earlierstudies.

When used to treat TD and other neuropsychiatric disorders it has beenused at dosages ranging from 1 gm to 3.6 grams per day (3 to 11 tabletsdaily) on a thrice-daily schedule. The average dose for treating TD hasbeen 3 grams daily. Prior to the instant technology, in general clinicalpractice no patient has had an optimal response on less than 2 grams perday.

The most common side effects of acamprosate are gastrointestinalsymptoms—including nausea, vomiting, diarrhea, and dyspepsia. Forpatients with alcoholism these side effects often lead to noncompliance,and in turn to decreased effectiveness of treatment. For patients withTD, who often are so distressed by their movements that they will adhereto effective treatment despite side effects, the gastrointestinal sideeffects make treatment unpleasant, or limit the acamprosate dose to onethat does not completely relieve their involuntary movements. For allpatient groups taking multiple pills three times daily is inconvenientand burdensome.

The gastrointestinal side effects of acamprosate are thought to be dueto the local irritation of the stomach and intestine by the drug, andnot due to central effects of the acetylhomotaurinate ion in the blood.Thus, enhancing the bioavailability of oral acamprosate can reduce thegastrointestinal side effects without compromising its efficacy.

Some embodiments provided herein relate to alternative formulations ofacamprosate that allow a smaller dose to be used, but that surprisinglyand unpredictably have sufficient or equal efficacy. Such formulationscan have greater bioavailability, for example, than the existingenteric-coated formulation.

Without being limited thereto, in some instances the greater therapeuticpotency of the new oral formulations can come from changes in the drug'sPK profile that allow the same therapeutic benefits to be obtained froma smaller total area under the time-concentration curve (AUC). Greateroral bioavailability, if it is attained, is an additional benefit thatmay enable even greater oral potency. However, what is surprising,unpredicted and unexpected here in some embodiments is the increase intherapeutic potency that is independent of any increase in oralbioavailability. Thus, in some embodiments, greater therapeutic potencyof oral formulations can be attained by altering the pharmacokinetics(PK) of the drug to make it more efficacious despite a smaller AUC inthe blood. In particular, some embodiments relate to formulations anddosage schedules that maintain the acamprosate concentration above athreshold for a sufficient time during each 24-hour day. Suchformulations and schedules are efficacious even though the acamprosateconcentration does not exceed the threshold for the entire 24 hourperiod.

There are at least several ways to reformulate drugs to alter their PKprofiles according to the instant technology. The technology describedhere relates to the use of any of such formulation technologies to alterthe PK profile of acamprosate in a way that makes it efficacious(including in some aspects, more efficacious) with a lower area underthe curve than that produced by three times daily administration of thecurrently-marketed enteric-coated formulation. This in turn makespossible the administration of lower oral doses of acamprosate—less thanone gram per day—on a less frequent schedule—once or twice daily—thanhas been described heretofore. The lower oral daily doses of acamprosatedescribed herein are not necessarily bioequivalent to higher daily dosesof enteric-coated acamprosate that have been previously shownefficacious for the various indications for the drug. In fact, in someembodiments the lower daily doses and once- or twice-daily scheduledescribed for the new formulations usually will produce a lower totalarea under the curve (AUC) than the therapeutically equivalent doses ofthe enteric-coated preparation given three times a day, so their equalefficacy is an unexpected finding.

The technology according to some embodiments described herein is basedon several original observations: (1) There are clinical cases in whichgiving the existing enteric-coated acamprosate to patients on atwice-daily schedule made a daily dose more efficacious than when givenon a thrice-daily schedule. Thus, it has been discovered that the shapeof the PK curve and not just the AUC can make a difference to efficacy.Specifically, that having a blood concentration above a threshold forseveral hours per day may be more efficacious than maintaining aconcentration just below that threshold for 24 hours a day. (2) In a dogmodel of a GR controlled release system applicable to a wide range of GRand controlled release technologies it was shown (see EXAMPLE 3 below)that controlled presentation of acamprosate over eight hours yielded asignificantly longer residence time above a threshold concentration thanimmediate release of the same dosage, even when there was not asignificant decrease in the AUC. In the model of controlled release, thedrug “saved” by avoiding a high C_(max) was distributed across severalhours, giving a several hour period in which the blood concentration ofacamprosate was higher than the blood concentration after administrationof a single dose of the immediate release version. (3) Clinicalobservations of TD cases where enteric coated acamprosate given threetimes daily had greater efficacy at a given daily dosage when the dailydosage was divided unevenly among the three doses. (4) The therapeuticaction of acamprosate in TD is based on its effects on glutamatetransmission. These effects are not based on direct interaction ofacamprosate with glutamate receptors, but rather on downstream effectsof acamprosate modulation at other sites on the neuron. These downstreameffects are based in part on modulation of RNA transcription, amechanism implying the potential for persistence of effect after thedrug is no longer present at a threshold level for clinical efficacy.

Further, a controlled release GR version of acamprosate can causesignificantly less GI side effects than the immediate-release version,since the maximum concentration of the drug in the gastric juice or inthe intestine will be lower than with the immediate release version.

It is known that immediate release acamprosate (which is equivalent toacamprosate solution because acamprosate is immediately and completelysoluble in gastric juice) has twice the bioavailability asenteric-coated acamprosate (Saivin S et al., Clinical Pharmacokineticsof Acamprosate, Clinical Pharmacokinetics Vol. 35, Number 5, November1998, pp. 331-345, which is incorporated herein by reference in itsentirety). The new observations and discoveries reported heredemonstrate that controlled release acamprosate delivered by a GR systemcan be at least 50% more potent than IR acamprosate for treating TD andother neuropsychiatric disorders. Thus, controlled release GRformulations can be efficacious at total daily doses of less than 1 gramper day, and these formulations can be given on a twice-daily schedule,and even on a once-daily schedule, depending on the threshold bloodlevel and daily time above that level required for efficacy in a givenpatient. The model system studied was based on gastric retention andcontrolled release over eight hours. It is evident that GR andcontrolled release over six hours or controlled release over four hourscan be satisfactory for therapeutic advantage, depending on the time andconcentration thresholds for efficacy in particular patient populationsand for particular indications.

The dog study of simulated GR acamprosate (EXAMPLE 3 below) showed thatcomparing the PK curve (time×plasma concentration curve) for simulatedGR acamprosate (intra-gastric administration of IR acamprosate everyhalf hour in amounts that decrease linearly with the square root oftime) with the PK curve for intra-gastric administration of the sametotal dose of IR acamprosate all at once, the curve for simulated GRacamprosate lies above the curve for IR acamprosate for more than sixhours (see PK plots from the dog study). Thus, the time above criticalthreshold is hours greater for simulated GR acamprosate than for IRacamprosate, for a significant range of values for the criticalthreshold. Furthermore, the area under the curve (AUC) for GRacamprosate usually is greater than the AUC for IR acamprosate—andsometimes significantly greater.

Enteric-coated acamprosate is only half as bioavailable as IRacamprosate and has a lower maximum concentration (C_(max)) and longertime to peak concentration (T_(max)) than IR acamprosate. GR acamprosatehas an even greater therapeutic advantage over enteric-coatedacamprosate than over IR acamprosate. Furthermore, the steady-stateconcentration in the blood when enteric-coated acamprosate is giventhree times a day is approached slowly over 5-7 days, with the plasmalevel of acamprosate during the first several days of administrationbelow the eventual steady-state plasma level. By contrast, a gastricretentive formulation of acamprosate according to embodiments describedherein that provides controlled delivery of acamprosate into the stomachand thence the duodenum—with a single dose can reach the blood level ofacamprosate attained only after several days on the enteric-coatedversion, and it might maintain that level for several hours. One or twodoses daily of the acamprosate formulations described herein can beefficacious even though the daily AUC might lie below the daily AUC forenteric-coated acamprosate dosed three times a day on an ongoing basis.

GR formulations of acamprosate can produce a PK curve almost identicalto that of simulated GR acamprosate if that formulation releasesacamprosate into gastric juice at a rate proportional to the square rootof time. Some embodiments herein relate to the use of any GR formulationthat releases acamprosate at such a rate (or close to it). Onenon-limiting example of a specific GR formulation described herein (seeEXAMPLE 6 below) does release acamprosate at such a rate (see forexample the tables showing the composition of the 400 mg and 800 mg GRacamprosate tablets tested; see the in vitro drug release data in twodifferent media—one highly acidic and typical of fasting gastric juiceand the other with a pH typical of gastric juice in the fed state). ThePK curve of such GR acamprosate in dogs (and in humans) lies above thePK curve for the same dose of IR acamprosate or of enteric-coatedacamprosate for several hours.

GR acamprosate can be more than twice as bioavailable as enteric-coatedacamprosate. Thus, less than 1.3 gm per day of GR acamprosate can havethe therapeutic effect of 2.6 gm of enteric-coated acamprosate, thelatter being the upper limit of dose ranges for acamprosate in thetreatment of TD and other neuropsychiatric disorders described inpreviously issued patents. Thus, dosing of GR acamprosate at 400 mgthree times a day can give therapeutic results equivalent to 2.6 gm perday of enteric coated acamprosate.

However, consistent with the human case set forth in EXAMPLE 1 thatevidences that there is a therapeutic threshold that need be exceededfor significantly less than 24 hours, for example, eight hours per 24hours, the dosing of 400 mg of GR acamprosate twice a day, or possibly800 mg once a day, can be effective. This results in the totalacamprosate dose for the GR formulation being below 1 gm per day—lessthan the previously recognized therapeutic range—even for a case thatwould require 2.6 gm per day of the enteric-coated formulation forefficacy, in a situation where the GR formulation at that dose did notproduce as high an AUC as 2.6 gm of the enteric-coated formulation.

Further, it should be understood that according to some embodiments thesub gram, twice or once a day regimens (e.g., 400 mg twice a day or 800mg once a day regimens) of GR acamprosate do not give equivalentconcentrations in the blood to those produced by enteric-coatedacamprosate given in a higher total daily dose on a three times dailyschedule. The latter would give—after 5-7 days—a stable level ofacamprosate, whereas the GR regimens can produce a fluctuating level ofacamprosate that might be below the steady state level forenteric-coated acamprosate, at some times of the day. Thus, the GRformulation given at less than 1 gm per day would not necessarily bebio-equivalent to the enteric-coated formulation given at dosages of 1gm to 2.6 gm on a three times a day schedule, and in fact it can evenhave a lower total AUC in 24 hours than that produced by 2.6 grams dailyof acamprosate. For these reasons the use of GR acamprosate at a dailydose of less than 1 gm per day given on a once-daily or twice-dailybasis is not suggested by the prior art, and its efficacy for TD (andfor other neuropsychiatric disorders) is a novel and unexpecteddiscovery.

The GR acamprosate formulations (e.g., tablets) according to someembodiments herein can thus be of size such that the total tablet orpill is easy to swallow. For example, the specifically describedformulations herein, in particular, 400 mg GR acamprosate tablets andeven 800 GR acamprosate tablets are small enough to be easily swallowed.They thus make possible reasonably-sized fixed-dose combination tabletscomprising GR acamprosate and another drug that is given in a lowerdosage than the GR acamprosate. In some embodiments these formulationsare novel compositions because they are made feasible by the reductionin daily acamprosate dose and dosage frequency made possible by the GRformulation of acamprosate and the finding that a threshold level ofacamprosate need not be maintained for 24 hours per day for efficacy.

Some embodiments of the present technology introduce a way to administera therapeutic dosage of acamprosate in one (relatively) small dose thatonly has to be taken once or twice daily. The smaller dosage form alsocan have ancillary benefits. First of all, the smaller dosage can leadto lesser side-effects. It also can lead to improved patient compliancedue to being taken fewer times each day, for example, once daily.Additionally, smaller dosage forms allow for more convenientco-administration of acamprosate with other drugs, for example as partof a single dosage form or as separate dosage forms.

Acamprosate Formulations

Some embodiments relate to formulations comprising acamprosate designedfor sustained or controlled release. Examples of sustained or controlledrelease pharmaceutical formulations that can be used with acamprosateinclude, for example, the materials and methods described in U.S. Pat.Nos. 3,536,809; 3,598,123; 3,845,770; 3,916,899; 4,008,719; 4,404,1834,690,820; 4,851,232; 4,861,598; 4,871,548; 4,970,075; 4,992,278;5,007,790; 5,059,595; 5,073,543; 5,120,548; 5,273,758; 5,354,556;5,458,887; 5,582,837; 5,591,767; 5,674,533; 5,718,700; 5,733,566;5,736,159; 5,783,212; 5,840,754; 5,912,268; 5,972,389; 6,120,803;6,340,475; 6,365,183; 6,403,120; 6,451,808; 6,488,962; 6,548,083;6,635,280; 6,635,281; 6,682,759; 6,723,340; 6,797,283; 7,405,238;7,413,751; 7,438,927; 7,514,100; 7,612,112; 7,731,989; Re.34,990; U.S.Pat. No. 7,736,667; and U.S. Pat. No. 7,976,870; U.S. Patent Pub Nos.20110091542; 20090304768; 20090304753; foreign patent publicationnumbers EP 0,661,045, A1; JP Kokei 61233632 and PCT publication numbersWO 9929297; WO 9912527; WO 9930692; WO 9921551; WO 9929305, WO 9917745;WO 9906045, WO 9833489; WO 9855107; WO 9811879; WO 9815264; WO 9737640;WO 9733566; WO 9748385; WO 9747285; WO 9718814; WO 9637202; WO 9637189;WO 9613248; WO 9608253; WO 9600065; WO 9626718; WO 9626717; WO 9632097;WO 9529665; WO 9519174; WO 9,591,174; WO 9530422; WO 9427587; WO9625153; each of which is incorporated herein by reference in itsentirety. In each of the listed patents and publications, acamprosate ina dosage of less than 1 gram (e.g., 100 mg to 900 mg) can be used as anactive agent replacing or in addition to other agents described in therespective document using the particular formulation technology that isdescribed, for example. In particular, the U.S. Pat. No. 7,514,100patent provides a description regarding how to incorporate varioustechnologies to obtain extended release formulations, and thedescription can be used for acamprosate formulations.

Some embodiments disclosed herein relate to pharmaceutical dosage formscomprising gastroretentive controlled release acamprosate at a specifieddosage in combination with a first generation neuroleptic ormetoclopramide at a specified dosage, with a second generationneuroleptic at a specified dosage, or with a serotonin reuptakeinhibitor (SSRI or SNRI drug) at a specified dosage.

Active Agent

The controlled release oral dosage forms of the present technologypreferably include less than 1 gram (e.g., from about 50 mg to 900 mg)acamprosate or an equivalent amount of a pharmaceutically acceptablesalt thereof, such as for example the magnesium, sodium, or lithiumsalt. For example, the dosage can be 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg or any value or sub range within that largerrange. As noted elsewhere herein, other salts are contemplated, as areanalogs of acamprosate and salts thereof.

If a second drug is included in the formulation, such drug may beincluded in controlled release form or in immediate release form. Theadditional drug may be incorporated into the matrix (e.g., controlledrelease matrix) along with the acamprosate; incorporated into a coating(e.g., a controlled release coating); incorporated as a separate band orlayer (e.g., a separated controlled release layer or immediate releaselayer); or may be incorporated as a powder, granulation, etc., in agelatin capsule with the substrates.

Dosage Forms

The controlled-release dosage form may optionally include a controlledrelease material which is incorporated into a matrix along with theacamprosate, or which is applied as a sustained release coating over asubstrate comprising the drug (the term “substrate” encompassing beads,pellets, spheroids, tablets, tablet cores, etc.). The controlled releasematerial may be hydrophobic or hydrophilic as desired. The oral dosageform may be provided as, for example, granules, spheroids, pellets orother multi particulate formulations. An amount of the multiparticulates which is effective to provide the desired dose ofacamprosate over time may be placed in a capsule or may be incorporatedin any other suitable oral solid form, e.g., compressed into a tablet.On the other hand, the oral dosage form may be prepared as a tablet corecoated with a controlled-release coating, or as a tablet comprising amatrix of drug and controlled release material, and optionally otherpharmaceutically desirable ingredients (e.g., diluents, binders,colorants, lubricants, etc.). The controlled release dosage form mayalso be prepared as a bead formulation or an osmotic dosage formulation.

Controlled Release Matrix Formulations

U.S. Pat. No. 7,514,100 (the '100 patent) describes in detail methods ofachieving controlled release formulations in dosages of drugs and isincluded by reference, herein. The '100 patent explains how to achieve acontrolled-release formulation via a matrix which includes a controlledrelease material—either a hydrophilic or hydrophobic material.

Controlled release can be accomplished by (a) forming granulescomprising at least one hydrophobic and/or hydrophilic material (e.g., awater soluble hydroxyalkyl cellulose) together with the acamprosate; (b)mixing the at least one hydrophobic and/or hydrophilic materialcontaining granules with at least one C₁₂-C₃₆ aliphatic alcohol, and (c)optionally, compressing and shaping the granules.

The matrices can also be prepared via melt pelletization,melt-granulation, or melt-extrusion techniques. The controlled releasematrix may also contain suitable quantities of other materials, e.g.,diluents, lubricants, binders, granulating aids, colorants, flavorantsand glidants that are conventional in the pharmaceutical art in amountsup to about 50% by weight of the particulate if desired. It may alsoinclude combinations of multi-particulates containing one or moredyskinesia treatments or cures.

In certain embodiments, a spheronising agent can be added to a granulateor to multi particulates and then spheronized to produce controlledrelease spheroids. The spheroids are then optionally over coated with acontrolled release coating by methods such as those described herein.

Preparation of Coated Bead Formulations

The '100 patent also explains that the oral solid controlled releasedosage form can comprise a plurality of coated substrates. An aqueousdispersion of hydrophobic material is used to coat the beads to providefor the controlled release of the acamprosate. The stabilizedcontrolled-release bead formulations slowly release the acamprosate,e.g., when ingested and exposed to preferably to gastric fluids, butalso to intestinal fluids. Substrates coated with a therapeuticallyactive agent are prepared, e.g. by dissolving the therapeutically activeagent in water and then spraying the solution onto a substrate.

Controlled Release Osmotic Dosage

Controlled release dosage forms may also be prepared as osmotic dosageformulations.

Coatings

The dosage forms as described herein may optionally be coated with oneor more coatings suitable for the regulation of release or for theprotection of the formulation. For instance, a coating can be added thatprovides for either pH-dependent or pH-independent release, e.g., whenexposed to gastrointestinal fluid. When a pH-independent coating isdesired, the coating is designed to achieve optimal release regardlessof pH-changes in the environmental fluid, e.g., the GI tract. Otherpreferred embodiments include a pH-dependent coating that releases theacamprosate in desired areas of the gastrointestinal (GI) tract, e.g.,the stomach or small intestine. It is also possible to formulatecompositions which release a portion of the dose in one desired area ofthe GI tract, e.g., the stomach, and release the remainder of the dosein another area of the GI tract, e.g., the small intestine.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials well suited for coating the substrates,e.g., beads, tablets, etc.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials well suited for coating the substrates,e.g., beads, tablets, etc.

Acrylic Polymers

In other preferred embodiments, the controlled release materialcomprising the controlled-release coating is a pharmaceuticallyacceptable acrylic polymer.

Plasticizers

In embodiments where the coating comprises an aqueous dispersion of ahydrophobic controlled release material, the inclusion of an effectiveamount of a plasticizer in the aqueous dispersion of hydrophobicmaterial will further improve the physical properties of thecontrolled-release coating.

The controlled-release coatings may also include an exit meanscomprising at least one passageway, orifice, or the like. The passagewaymay be formed by such methods as those disclosed in U.S. Pat. Nos.3,845,770; 3,916,889; 4,063,064; and 4,088,864; each of which isincorporated herein by reference in its entirety. The passageway canhave any shape such as round, triangular, square, elliptical, irregular,etc.

Since acamprosate is absorbed in the intestinal tract, controlledrelease of the drug preferably entails or in some cases may require,among other things, that the drug dosage form be maintained in thestomach for a number of hours. Without any modifications, the transittime of an oral dosage form in the stomach is less than three hours. WenH, Park, K Oral Controlled Release Formulation Design and Drug Delivery:Theory to Practice.) Therefore, a preferred method of accomplishingcontrolled release is to deliver it with a gastroretentive drug dosagesystem. Several approaches to gastroretentive drug dosage systems aredescribed in Surana A S, Kotecha R K An Overview on Various Approachesto Oral Controlled Drug Delivery System Via Gastroretention. Int'l. J.Pharm. Sci. Rev. and Research 2010; 2:68-72 and U.S. Pat. App.2005/0249798, now abandoned; each of which is incorporated herein byreference in its entirety.

The first (and most common) is a floating drug delivery system, whichworks by using a low density system so that the drug-containing systemhas sufficient buoyancy to float over the gastric contents and remainsin the stomach for a prolonged period. There are two ways to make abuoyant system. The first is an effervescent system and the second is anon-effervescent system.

In effervescent systems the buoyancy is achieved by using swellablepolymers such as METHOCEL® or polysaccharides, and effervescentcomponents or liquids that gasify at body temperature. When the systemreaches the stomach gas is released into the polymers—e.g. becausereaction in the strongly acidic stomach causes gas release or because aliquid gasifies at body temperature-and this maintains the system'sbuoyancy. Such methods are described, e.g., in U.S. Pat. Nos. 3,901,232,3,944,064, 4,996,058, 5,651,985 and German Offenlegungsschrift (DE-A)No. 3,527,852; each of which is incorporated herein by reference in itsentirety. The very same material that swells can also be one that slowlyerodes, thus delivering a controlled release system.

In non-effervescent systems a high level of gel-forming, highlyswellable, cellulosic hydrocolloids, polysaccharides, or matrix-formingpolymers are used. When they reach the stomach the compounds “hydrateand form a colloidal gel barrier that controls the rate of fluidpenetration into the device and consequent drug release.” The trappedair confers buoyancy. As the exterior of the drug delivery devicedissolves, the interior swells, thus maintaining the buoyancy. The slowerosion can also be used to deliver a controlled release of the drug.Hydrophilic polymers that swell upon intake of water from gastric fluidshave been previously described, for example, U.S. Pat. Nos. 6,723,340,6,488,962, 6,340,475 and 6,635,280; each of which is incorporated hereinby reference in its entirety. These patents disclose systems wherein thedosage form swells to a size large enough that it remains in the stomachbecause it cannot pass through the pyloric sphincter when the sphincteris contracted, such as in the fed mode. As a result, the dosage remainsin the stomach for at least four hours. These formulations may bedesigned to produce desired release and delivery profiles for bothhighly soluble and poorly soluble drugs.

The second system is a bio/mucoadhesive system, which works by using asubstance that binds to the gastric mucosa (either to mucous cellmembranes or to the mucus secreted by them), thus increasing thesystem's residence in the stomach. Bioadhesive polymers bind either tothe membranes; mucoadhesive polymers bind to the mucus lining.

In some embodiments, the characteristics of these polymers are, forexample, molecular flexibility, hydrophilic functional groups, andspecific molecular weight, chain length, and conformation. Furthermore,in some embodiments, they can be nontoxic and nonabsorbable, can formnoncovalent bonds with the mucin-epithelial surfaces, can have quickadherence to moist surfaces, can easily incorporate the drug and offerno hindrance to drug release, and have a specific site of attachment,for example.

There are three broad categories of bio/mucoadhesive systems:hydration-mediated adhesion, bonding-mediated adhesion andreceptor-mediated adhesion.

In hydration-mediated adhesion, the binding substance is a swellablepolymer that absorbs large amounts of water and therefore becomessticky. Bonding-mediated adhesion is achieved either through physical orchemical binding. In physical binding the adhesive material inserts intocrevices or folds of the mucosa. In chemical bonding the bindingsubstance forms chemical bonds (either covalent, ionic, or hydrogenbonds or van der Waals interactions). Finally, in receptor mediatedadhesion the binding substance directly binds to specific receptor cellsin the mucus or the gastrointestinal tract. For instance, certain plantlectins bind sugar groups present in the mucus or on the glycocalyx.These can be combined with ion exchange resins. (Burton S; Washington N;Steele R J C; Musson R; Feely L, J. Phar. Pharm. 47, 901; which isincorporated herein by reference in its entirety.)

A third method to obtain gastroretentive drug dosage systems is to use aswelling/expanding system where the dosage form swells so that it cannotpass through the pylorus, and is consequently stuck in the stomach. Theswelling can be obtained by using a polymer that swells when in contactwith water, but that has crosslinks in the hydrophilic polymer networkto prevent the dosage form from coming apart and dissolving. A balancebetween the extent and the duration of the swelling is achieved byselecting the amount of cross linking. If there are many crosslinks, thesystem will swell poorly but last for a long time. Conversely, if thereare few crosslinks, the system will swell will but will dissolve morerapidly. Eventually, the system will dissolve either because ofinteractions with the gastric juice or because of abrasion with otherparticles in the stomach. Such swelling mechanisms are described, e.g.,in U.S. Pat. Nos. 3,574,820, 4,207,890, 4,434,153, 4,767,727, 4,735,804,4,758,436, 5,002,772, 5,047,464, 5,217,712, 5,443,843, 5,651,985,6,685,962, 7,736,667, 7,976,870 and German Pat. No. 2,328,580; each ofwhich is incorporated herein by reference in its entirety. A similarapproach is suggested by U.S. Pat. App. 2005/0249798, now abandoned, andU.S. Pat. Apps. 2009/0304753 and 20090304768; each of which isincorporated herein by reference in its entirety; wherein the drugdevice is a folded sheet that unfolds (in some embodiments like anopening accordion) when it swells. The very same material that swellscan also be one that slowly erodes, thus delivering a controlled releasesystem if the drug is distributed throughout the pill.

A fourth approach is to use a high density dosage form where the drugdosage form sinks to the bottom of the stomach and is entrapped in thestomach folds, thus allowing it to withstand the peristaltic waves ofthe stomach wall. Examples of high density components that are added toobtain high density drug dosage forms are barium sulphate, zinc oxide,iron powder, and titanium dioxide.

The final approach is a magnetic system. The drug is administered with asmall internal magnet or magnetizable element. An external magnet isplaced over the stomach thus preventing the drug dosage form fromtravelling past the stomach.

Using one of these methods for achieving gastric retention of the drugdelivery system, it next can be necessary to achieve controlled releaseof the active pharmaceutical ingredient. There are a number of potentialmethods; these are reviewed in the monograph Wen H, Park, K OralControlled Release Formulation Design and Drug Delivery: Theory toPractice, which is incorporated herein by reference in its entirety.

The first method is to use dissolution-controlled formulations. Oneapproach is the encapsulated dissolution system where a system comprisedof many small beads is coated with a dissolvable material, such as apolymer. The beads are of varying thickness, so that the outer layers ofthe various beads dissolve at different times (because of the differentthicknesses among the beads). The beads can be compressed into tabletsor filled into capsules. Alternatively, a matrix dissolution system canbe used, wherein the drug is homogenously distributed throughout thepolymer matrix. As the polymer dissolves, the drug trapped in that partof the polymer is released.

The second method is diffusion-controlled formulations, where the drughas to diffuse through a polymer membrane or matrix to be released. Thefirst approach to diffusion-controlled formulations is a reservoirsystem, wherein the drug is surrounded by a polymer membrane.Alternatively, a monolithic system can be used, wherein the drug isdistributed through the polymer matrix.

A third method is osmosis-based formulations, wherein the drug issurrounded with a semi permeable membrane, such as cellulose acetate,with at least one small orifice. Only water can diffuse through themembrane, so the concentration of water in the dosage form increases andthe drug, dissolved in the water, seeps out of the orifice at acontrolled rate.

A fourth method is ion exchange-based formulations, wherein the drug isionically bound to an ion-exchange resin that is water-insoluble. Thedrug is released when other ions with the same charge bind the resin.Finally, some of these methods can be combined. For instance, it ispossible to cover an ion-exchange resin with a diffusion controlledformulation.

The PK of acamprosate delivered by any of these formulations can beexpected to be similar to that produced by the administration of IRcapsules containing a fraction of the total dose, on a periodic basis atintervals of 30 minutes or less. Thus, the procedure used in the dog PKstudy reported herein can be a model for the PK to be obtained from anyof the formulations described here.

Acamprosate delivered by a GR system can be efficacious for treatingtardive dyskinesia and other neuropsychiatric indications if it is givenat a dose sufficient to give blood concentrations greater than or equalthan those produced by an effective dose of the currently-marketedenteric-coated preparation. A dose and dosing schedule cannot be assumeda priori to be efficacious if it does not produce equal or greaterconcentrations.

Two clinical cases demonstrate that the efficacy of acamprosate for itsneuropsychiatric indications can depend on having an adequate bloodlevel of the drug for substantially less than 24 hours a day. As such,GR preparations of acamprosate capable of maintaining a blood levelabove a target concentration for 8 hours a day can be effective givenonce or at most twice a day. Now, the AUC for IR acamprosate in humansis twice the AUC for the currently-marked enteric-coated acamprosateutilized in the cases described in previous patents on neuropsychiatricuses of acamprosate, and the AUC for the same dose of GR acamprosate canbe at least as high as that—and perhaps higher in some cases, as shownin the dog study PK study described herein conducted by the inventors.The case shows that if an effective dose of acamprosate is divided intothree equal parts, then one or two of those parts will suffice to treatthe disorder if they are formulated as a GR controlled-release systemthat deliver the dose over eight hours in a manner that produces anessentially flat time-concentration curve. If so, less than one-third ofthe dose given using the currently-marketed enteric-coated version canhave the same efficacy. The dosage range specified to date for treatingneuropsychiatric disorders with enteric-coated acamprosate is 1 to 2.6grams. The above considerations show efficacy with a daily dose of GRacamprosate of less than 1 gram per day given on a once or twice per daybasis. An efficacious dose can potentially be as low as 100 mg once aday, if in a given case 1 gram per day of the enteric-coated formulationis efficacious and a single daily dose of the GR formulation that was ⅓of the total daily dose was efficacious, and overall bioavailability ofthe GR formulation was 40% higher than with an IR formulation (a numberwithin the range suggested by the dog study reported herein.

Any of the foregoing mixtures and compositions can be appropriate intreatments and therapies in accordance with the invention disclosedherein, provided that the active ingredient in the formulation is notinactivated by the formulation and the formulation is physiologicallycompatible and tolerable with the route of administration. See alsoBaldrick P. “Pharmaceutical excipient development: the need forpreclinical guidance.” Regul. Toxicol. Pharmacol. 32(2):210-8 (2000),Charman W N “Lipids, lipophilic drugs, and oral drug delivery-someemerging concepts.” J Pharm Sci 0.89(8):967-78 (2000), and the citationstherein for additional information related to formulations, excipientsand carriers well known to pharmaceutical chemists.

As noted herein the formulations can include various materials. Amongsuch materials are fillers. In some embodiments, the compositions caninclude one or more fillers, for example, microcrystalline cellulose,lactose, a compressible sugar, xylitol, sorbitol, mannitol,pregelatinized starch, maltodextrin, calcium phosphate dibasic, calciumphosphate tribasic, calcium carbonate DC, a calcium silicate, acombinations of one or more of the same, or the like. In one aspect ofthis embodiment, the at least one filler can be microcrystallinecellulose. The microcrystalline cellulose (other filler or combinationof fillers) can be provided in an amount of about 8% to about 90% w/w.The precise amount can depend upon the amount of the acamprosate and/orthe amounts of other excipients or materials, for example. Thecompositions can further comprise at least one of the following secondfillers, lactose, compressible sugars, xylitol, sorbitol, mannitol,pregelatinized starch, maltodextrin, calcium phosphate dibasic, calciumphosphate tribasic, calcium carbonate DC, a combinations of one or moreof the same, or the like.

Any other suitable excipient(s) may be used in the formulation. Forexample, excipients suitable for use include, but are not limited to,binders, diluents, disintegrants, lubricants, fillers, carriers, and thelike.

In one embodiment, the formulation comprises a mixture of theacamprosate in a gastric retentive and/or controlled releaseformulation. Such formulations can include any of the substancesdescribed herein, and additional processing aides, such as, for example,magnesium stearate and colloidal silicon dioxide, and optionally,colorant(s). For example, in some embodiments, colloidal silicondioxide, may be added separately to the formulation as a glidant.Without being limited thereto, colloidal silicon dioxide can be added atconcentrations ranging from about 0.1% to about 5.0% w/w, or from about0.25% to about 2% w/w, or from about 0.5% to about 1% w/w.

In some embodiments, magnesium stearate can be added as a lubricant, forexample, to improve powder flow, prevent the blend from adhering totableting equipment and punch surfaces and provide lubrication to allowtablets to be cleanly ejected from tablet dies. Magnesium stearate cantypically be added to pharmaceutical formulations at concentrationsranging from about 0.1% to about 5.0% w/w, or from about 0.25% to about2% w/w, or from about 0.5% to about 1.25% w/w.

In some embodiments, color additives also can be included. The colorantscan be used in amounts sufficient to distinguish dosage form strengths.Preferably, color additives approved for use in drugs (21 CFR 74, whichis incorporated herein by reference in its entirety) are added to thecommercial formulations to differentiate tablet strengths. The use ofother pharmaceutically acceptable colorants and combinations thereof areencompassed by the current invention.

Binders can be used, for example, to impart cohesive qualities to aformulation, and thus ensure that the resulting dosage form remainsintact after compaction. Suitable binder materials include, but are notlimited to, microcrystalline cellulose, gelatin, sugars (including, forexample, sucrose, glucose, dextrose and maltodextrin), polyethyleneglycol, waxes, natural and synthetic gums, polyvinylpyrrolidone,cellulosic polymers (including, for example, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose,and the like).

One of ordinary skill in the art would recognize additional bindersand/or amounts that can be used in the formulations described herein. Aswould be recognized by one of ordinary skill in the art, whenincorporated into the formulations disclosed herein, the amounts of themajor filler(s) and/or other excipients can be reduced accordingly toaccommodate the amount of binder added in order to keep the overall unitweight of the tablet unchanged. In one embodiment, the binder(s) is(are)sprayed on from solution, e.g. wet granulation, to increase bindingactivity.

Disintegrants can be used, for example, to facilitate tabletdisintegration after administration, and are generally starches, clays,celluloses, algins, gums or crosslinked polymers. Suitable disintegrantsinclude, but are not limited to, crosslinked polyvinylpyrrolidone(PVP-XL), sodium starch glycolate, and croscarmellose sodium. Ifdesired, the pharmaceutical formulation can also contain minor amountsof nontoxic auxiliary substances such as wetting or emulsifying agents,pH buffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate,sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylenesorbitan fatty acid esters, etc. and the like. One of ordinary skill inthe art would recognize additional disintegrants and/or amounts ofdisintegrants that can be used in the formulations described herein. Aswould be recognized by one of ordinary skill in the art, whenincorporated into the formulations disclosed herein, the amounts of themajor filler(s) and/or other excipients can be reduced accordingly toaccommodate the amount of disintegrant added in order to keep theoverall unit weight of the tablet unchanged.

In some embodiments, the formulations can include a coating, forexample, a film coating. Where film coatings are involved, coatingpreparations can include, for example, a film-forming polymer, aplasticizer, or the like. Also, the coatings can include pigments and/oropacifiers. Non-limiting examples of film-forming polymers includehydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinyl pyrrolidine, and starches. Non-limiting examples ofplasticizers include polyethylene glycol, tributyl citrate, dibutylsebecate, castor oil, and acetylated monoglyceride. Furthermore,non-limiting examples of pigments and opacifiers include iron oxides ofvarious colors, lake dyes of many colors, titanium dioxide, and thelike.

One can also prepare or administer the compounds of the invention insustained-release forms or from sustained-release drug delivery systems.A description of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

As mentioned above, the compositions and formulations disclosed hereinalso can include one or more pharmaceutically-acceptable carriermaterials or excipients. Such compositions can be prepared for storageand for subsequent administration. Any acceptable carriers or diluentsfor therapeutic use can be used, including those described, for example,in the incorporated material of Remington: The Science and Practice ofPharmacy (2003), which is incorporated herein by reference in itsentirety. The term “carrier” material or “excipient” herein can mean anysubstance, not itself a therapeutic agent, used as a carrier and/ordiluent and/or adjuvant, or vehicle for delivery of a therapeutic agentto a subject or added to a pharmaceutical composition to improve itshandling or storage properties or to permit or facilitate formation of adose unit of the composition into a discrete article such as a capsuleor tablet suitable for oral administration. Excipients can include, byway of illustration and not limitation, diluents, disintegrants, bindingagents, adhesives, wetting agents, polymers, lubricants, glidants,substances added to mask or counteract a disagreeable taste or odor,flavors, dyes, fragrances, and substances added to improve appearance ofthe composition. Acceptable excipients include lactose, sucrose, starchpowder, maize starch or derivatives thereof, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose,mannitol, lactose, lecithin, albumin, sodium glutamate, cysteinehydrochloride, and the like. Examples of suitable excipients for softgelatin capsules include vegetable oils, waxes, fats, and semisolid andliquid polyols. Suitable excipients for the preparation of solutions andsyrups include, without limitation, water, polyols, sucrose, invertsugar and glucose. Suitable excipients for injectable solutions include,without limitation, water, alcohols, polyols, glycerol, and vegetableoils. The pharmaceutical compositions can additionally includepreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorings, buffers, coating agents, orantioxidants. Sterile compositions for injection can be formulatedaccording to conventional pharmaceutical practice as described in theincorporated material in Remington: The Science and Practice of Pharmacy(2003). For example, dissolution or suspension of the active compound ina vehicle such as water or naturally occurring vegetable oil likesesame, peanut, or cottonseed oil or a synthetic fatty vehicle likeethyl oleate or the like may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

The compound can also be made in microencapsulated form. In addition, ifdesired, the injectable pharmaceutical compositions may contain minoramounts of nontoxic auxiliary substances, such as wetting agents, pHbuffering agents, and the like. If desired, absorption enhancingpreparations (for example, liposomes), can be utilized.

Enhancement of Gastric Retention Using Fed Mode Inducing Agent

Gastric retentive drug delivery systems can have improved function whenthe patient is in the fed mode, when the stomach does not produce theintense peristaltic contractions of Phase III of the Migrating MotorComplex (MMC). However, food can diminish the bioavailability ofacamprosate by approximately 30%. Without intending to be bound bytheory, although the mechanism of the food effect on acamprosatebioavailability is unknown, it is likely to be related to competitionfor a passive transport mechanism of limited capacity. The inventorshave determined that for even more optimal pharmacokinetics andbioavailability of acamprosate, the fed mode can be induced affectingthe MMC without interfering with the absorption of acamprosate in theway that a full meal would.

Accordingly, in some embodiments, an agent is co-administered withacamprosate to induce a “fed mode” in the stomach, inhibitingcontractions of the MMC and increasing gastric retention time. In someembodiments, the fed mode inducing agent is any suitable fed modeinducing agent, including without being limited thereto any of thosedescribed in U.S. Pat. No. 7,405,238, the content of which isincorporated herein by reference in its entirety. For example, the fedmode inducing agent can be an agent selected from the group consistingof one or more of: (a) glycine, glycylglycine, and salts of either ofthese two compounds (b) C4-C8 sugar alcohols (c) alkali and alkalineearth metal docusates (d) beta-casomorphins (e) dithioorganic acids suchas alpha-lipoic acid (racemic mixtures, enantiomers such as the Renantiomer, or enriched enantiomeric mixtures). In typical embodiments,the fed mode inducing agent is alpha-lipoic acid, for example. In someembodiments, alpha-lipoic acid can be administered in a dosage of about40 mg to 700 mg or any value or sub range there between. For example,40, 50, 60, 70, 80, 90, 100, 120, 130, 140, 150, 160, 170, 180, 190,200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,340, 350, 360, 370, 380 390, 400, 450, 500, 550 to about 600 mg, or anyvalue or sub range there between. In some aspects, the alpha-lipoic acidis in a dosage of from about 100 to about 300 mg, for example, or anyvalue or sub range there between. In some aspects, the alpha-lipoic acidis given in its racemic form; in other aspects it is given as its Renantiomer. In some aspects, the alpha-lipoic acid is included in agastric-retentive composition. In some aspects, the alpha-lipoic acid isat least partially in the coating of the gastric-retentive system. Insome aspects, the alpha-lipoic acid is incorporated into agastric-retentive system. In some aspects, the gastric-retentive systemis designed to release the alpha-lipoic acid within a desired period oftime, for example, the first hour after ingestion or any time periodwithin the first hour, for example. In some aspects, alpha-lipoic acidis included in combination with acamprosate, for example, acamprosate ina dose of less than 1 gram (e.g., of 100 to 700 mg), or any value or subrange there between. In some aspects, alpha-lipoic acid is included incombination with acamprosate and further in combination with aneuroleptic (antipsychotic) drug. In some aspects, alpha-lipoic acid isincluded in combination with acamprosate and a serotonin reuptakeinhibitor drug (SSRI or SNRI).

As exemplified in EXAMPLE 10 below, and as taught in the incorporatedmaterials of U.S. Pat. No. 7,405,238, any suitable fed mode inducingagent can be utilized as an immediate-release coating of agastric-retentive tablet. While not intending to be bound by theory, itis believed that when a fed mode inducing agent such as alpha-lipoicacid is incorporated into an immediate-release coating of agastric-retentive tablet containing acamprosate, almost all of thealpha-lipoic acid would pass through the duodenum hours before most ofthe acamprosate would reach the duodenum; therefore it would be expectedthat little or no reduction in acamprosate bioavailability would occur,even if alpha-lipoic acid and acamprosate potentially compete for thesame limited-capacity passive transport system. (In fact it is not knownwhether there is a common transporter.).

A dosage of alpha-lipoic acid in the range of about 40 mg to about 600mg, about 60 mg to about 500 mg, about 80 mg to about 400 mg, or about100 to about 300 mg (or any value or sub range there between any ofthose ranges and values) can be suitable when used as an immediaterelease component of a gastric retentive acamprosate tablet. Forexample, when alpha-lipoic is incorporated as a coating for the tablet,such a formulation can allow the patient to enjoy the pharmacokineticbenefits of GR acamprosate while taking the pill on an empty stomach.

As a non-limiting example, a GR acamprosate tablet can contain 350 mg ofacamprosate in a swellable matrix, coated with mixture of inertingredients and 150 mg of R-alpha-lipoic acid. Two such tablets taken,for example, once a day can provide the same therapeutic benefit as twoto three grams of enteric-coated acamprosate tablets (6 to 9 pills,taken on a thrice-daily schedule), in the treatment tardive dyskinesiaor other neuropsychiatric disorders. The two pills could be taken atbedtime or on awakening; thus the patient would take the medication, forexample, once daily, at home. This schedule can greatly enhanceconvenience and treatment adherence.

For example, in the case of alcoholism treatment, strict compliance withtreatment can be especially critical. Thus, the instant methods andcompositions, which can provide greater convenience, ease of use, andcompliance can result in better treatment for such patients. In fact,some embodiments of the technology described herein relate to methodsand compositions for the treatment of alcohol dependence. Theacamprosate can be formulated as set forth herein in a dosage as setforth herein. For example, the dosage can be up to 2-3 grams per day,but in some embodiments when formulated as described herein, it can beless than one gram per day, for example 40-700 mg or any subvalue or subrange therein. The improved adherence and/or convenience can be true andapplicable for other conditions regardless of whether compliance is asimportant as in the case of treating alcohol dependence. The fact thatthe methods and compositions can provide improved convenience andcompliance can be beneficial to many conditions that can be treated withacamprosate.

Other nutrients and drugs, including many described in the specificationfor U.S. Pat. No. 7,405,238 (incorporated herein in its entirety), canbe used in place of alpha-lipoic acid. In particular embodiments,alpha-lipoic acid is used as the fed mode inducing agent. For example,alpha-lipoic acid is very safe. Second, the metabolic effects ofalpha-lipoic acid can be of specific benefit in mitigating the sideeffects of antipsychotic drugs. Alpha-lipoic acid is an antioxidant, andoxidative stress is one of the mechanisms of neuroleptic-inducedcellular damage to the basal ganglia that can cause TD. Additionally,alpha-lipoic acid has hypoglycemic actions that can mitigate thepotential adverse effects of neuroleptics on glucose metabolism.

EXAMPLES Example 1

Case 1: A 56-year old woman had long-standing tardive dyskinesia inducedby treatment of schizoaffective disorder with a variety of neurolepticsand mood stabilizers. Her TD was characterized by side to side movementsof the jaw, grimacing movements, rocking of the trunk, and continualinvoluntary kicking, leg-crossing, and twisting movements of her legsand feet. At the time she presented for treatment of her TD she wastreated for her mental illness with lamotrigine and quetiapine, asecond-generation neuroleptic. She was started on acamprosate 666 mgthree times a day, with partial relief of symptoms. When acamprosate wasincreased to 999 mg three times a day she had complete relief of her TD.After two months free of symptoms of TD she switched from quetiapine toperphenazine, a first-generation neuroleptic; her TD symptoms did notreturn.

After additional weeks free of TD symptoms she discontinued theacamprosate. Her TD symptoms returned, as did feelings of anxiety andagitation that had not been present while she was on the combination ofacamprosate and perphenazine.

She resumed acamprosate, again finding that 666 mg three times a day didnot give her complete relief, but 999 mg three times a day did. On thisdose she again got relief of anxiety and agitation.

To test the hypothesis that the efficacy of acamprosate was related toadequate time above a threshold blood level the patient was asked to trytaking 1332 mg of acamprosate once a day. On this dose she continued tobe free of involuntary movements of TD, but did have significant GI sideeffects of diarrhea and abdominal cramps.

The results showed efficacy of acamprosate for TD at a lower total dailydose, when instead of distributing the dose evenly, a larger proportionof the dose was given at one time. This demonstrates that the use ofacamprosate at a concentration above a therapeutic threshold value for asufficient number of hours per 24-hour day (e.g., 6-14 hours, preferablyabout 8) is sufficient to give a 24-hour therapeutic effect.

Example 2

CASE 2: A 34-year old man had been treated with acamprosate for severalyears for TD due to exposure to several neuroleptics for schizoaffectivedisorder. He was currently treated with lamotrigine and quetiapine forhis mental illness, and was taking acamprosate 1032 mg+999 mg+1032 mg ona three times daily basis. This dose of acamprosate completely relievedhis involuntary movements of TD—the latter including involuntarymovements of the cheeks and mouth, rocking movements of the trunk, andtwisting movements of the both upper and lower extremities. 999 mg threetimes a day did not give full relief from his involuntary movements. Totest the therapeutic threshold hypothesis the patient was asked to try1032 mg of acamprosate once a day in the morning. On this dose he wasfree of movements in the morning and early afternoon but movementsreturned in the evening. When he added a second dose of 1032 mg in thelate afternoon—8 to 10 hours after his first dose—he obtained completerelief of symptoms. He noted that when be got relief of his involuntarymovements be also had less anxiety and agitation than when the movementswere present.

Both of these cases support two hypotheses: 1) That the treatmentresponse to acamprosate in TD (and presumably in other neuropsychiatricdisorders characterized by recurrent unwanted stereotypic symptoms) isrelated to the amount of time the acamprosate level is above a specificthreshold, and not on the AUC of the PK curve. This is so because inboth cases the patient did better on regimens that had a lower totaldaily dose of acamprosate but higher individual doses. This isunexpected, because it has not been known heretofore that lower totaldaily doses of acamprosate could work better than higher ones if theformer were given once or twice a day and the latter were given threetimes a day. (2) That the combination of acamprosate with a neurolepticcan provide relief of anxiety and agitation associated with psychosisand TD. This is unexpected, because though acamprosate by itself doesnot have anti-anxiety effects.

Combining the results from the dog study with the implications of thereported cases we can infer that acamprosate delivered by a GR systemcan relieve symptoms of TD and other neuropsychiatric disorders givenonce or twice a day. Considering the fact that the AUC from a singledose of acamprosate via a GR system can be more than twice the AUC froma single dose of the existing enteric-coated tablet formulation ofacamprosate it appears that a total daily dose of less than one gram ofGR acamprosate, given on either a once or twice a day basis would beadequate to treat TD in the case examples. Therefore in somecases—probably the majority of cases—of TD cases the minimum effectivedaily dose of acamprosate delivered by a GR controlled release systemcan be less than 1 gram—the minimum of the range of efficacious dosagesreported heretofore for the enteric-coated formulation. It should benoted further that experience to date with the enteric-coated tabletshas never shown them to fully relieve the symptoms of TD at doses of 1gram, whereas here in some embodiments daily doses of less than 1 gramcan offer complete symptom relief and not just a detectable therapeuticeffect.

Example 3

A pharmacokinetic study was conducted in four dogs. Dogs were givenimmediate-release (IR) acamprosate capsules orally. On one day they weregiven a single capsule containing 325 mg of acamprosate. On another dayone week later the dogs were given 325 mg of acamprosate divided intosmaller doses administered every 30 minutes, as shown in Table 1 below.

This mode of delivering acamprosate mimics the delivery of acamprosateinto the stomach by a controlled-release GR system. FIGS. 1-4 aretime-concentration curves for each of the dogs that compare IRacamprosate with simulated GR controlled-release acamprosate.

Table 2 shows pharmacokinetic parameters of the two delivery versions ofacamprosate in each of the four dogs and displays ratios of interestbetween the two versions for several parameters of interest. In thetable the residence time above two arbitrarily selected thresholds—2000ng/mL and 3000 ng/mL was calculated by measuring the graphs; an asterisknext to the residence time indicates that the residence time comprisedtwo discrete segments rather than a single contiguous period. The AUCwas always greater for the simulated GR system, though the difference intwo of the four dogs would be clinically insignificant. In one case thedifference was more than twofold. These differences in a small sampleare in accord with the well-known variability of acamprosate absorptionbetween individuals. The C_(max) was always significantly lower for thesimulated GR system even when the AUC was significantly higher. Theresidence time above either of the two thresholds was significantlyhigher for the GR system.

TABLE 1 SIMULATION OF A GATRORETENTIVE CONTROLLED RELEASE SYSTEM BYHALF-HOURLY ADMINISTRATION OF IMMEDIATE RELEASE ACAMPROSATE AcamprosateTime (h) Dosage (mg) 0.0 81.2 0.5 33.6 1.0 25.8 1.5 21.8 2.0 19.2 2.517.3 3.0 15.9 3.5 14.8 4.0 13.9 4.5 13.2 5.0 12.5 5.5 12.0 6.0 11.5 6.511.1 7.0 10.7 7.5 10.3 Total dose 324.8

TABLE 2 SELECTED PK PARAMETERS FROM DOG STUDY OF IR VERSUS GRCONTROLLED-RELEASE ACAMPROSATE AUClast AUCinf Hours over Hours overTreatment Dog No Tmax (h) Cmax (ng/mL) (h * ng/mL) (h * ng/mL) Cmax/AUC3000 ng/mL 2000 ng/mL IR 1 1 7380 31939 34283 23% 2.6 3.5 IR 2 1 715031829 41542 22% 2.4 2.9 IR 3 1 7550 35345 35739 21% 1.8 2.6 IR 4 1 492015929 16029 31% 1.8 2.6 GR-CR 1 5 4620 35185 35320 13% 5.3 7.9 GR-CR 2 85140 44221 46714 12% 6.8 9.7 GR-CR 3 6 4510 39182 43682 12% 4.4 6.8GR-CR 4 6 3290 32243 32806 10% 2.6 8.8 GR/IR 1 63% 110% 103% 200% 225%GR/IR 2 72% 139% 112% 288% 330% GR/IR 3 60% 111% 122% 250% 256% GR/IR 467% 202% 205% 150% 333% Peak Ratios Biovailability Ratios Residence TimeRatios

Example 4

Table 3 lists gastroretentive (GR) technologies capable of deliveringacamprosate so as to give a nearly constant level of the drug for fourhours or more. Table 4 lists examples of controlled-release technologiesthat can be applied in conjunction with the gastroretentive technologiesto produce the formulations utilized in embodiments described herein.

TABLE 3 GASTRORETENTIVE TECHNOLOGIES. 1) Floating - non-effervescent 2)Floating - effervescent 3) Bioadhesive 4) Mucoadhesive 5) Swelling 6)Expanding 7) Magnetic

TABLE 4 CONTROLLED-RELEASE TECHNOLOGIES. 1) Matrix 2) Coated beads 3)Osmotic 4) Ion exchange

Example 5

Composition of gastric retentive formulation of acamprosate calcium. Thetablets swell when they come in contact with gastric juices; they areretained in the stomach for several hours if they are administered inthe fed state (e.g., at the conclusion of a meal). The formulation hasbeen manufactured as 400 mg and 800 mg tablets. These are standard roundbi-convex white tablets with beveled edges. Both tablet strengths arespray coated with Opadry® II White (Colorcon, Inc.) for ease ofswallowing. Purified water is the vehicle for the Opadry®; it evaporatesduring the coating process. The total weight of the coating is between2% and 4% of the pre-coating weight.

The tablets prior to coating comprise the ingredients in the followingtable:

TABLE 5 Amount Amount (mg) in (mg) in 400 mg 800 mg Ingredient Functiontablet tablet Acamprosate calcium Active ingredient 400 800 PovidoneK-90 Binder 50 50 Microcrystalline cellulose Diluent 320 100 Colloidalsilicon dioxide Glidant 10 10 Citric acid Acidulant 60 0 CARBOPOL ® 974PPolymer 60 60 Carboxymethylcellulose Polymer 40 40 STARCAP 1500 ®Disintegrant 40 40 Talc powder Filler 10 10 Magnesium stearate Lubricant10 10 Total prior to coating 1000 1120

Example 6

Dissolution profiles of the 400 mg and 800 mg GR acamprosate tablets.400 mg or 800 mg tablets were dissolved in either acetate solution (pH4.5) or 1N HCl (pH 1.0). The percentage of the active ingredientreleased into the solution was determined at 1, 2, 4, 6, 8, and 10hours. Each release profile was assessed in six different test vessels.The following tables display the results, demonstrating that release isapproximately linear with the square root of time. The fourth column ineach table displays the amounts of drug that would be released if therelease were exactly proportional to the square root of time, with aspecified coefficient that ranges from 0.27 to 0.3.

TABLE 6 Release of Acamprosate from 400 mg Tablets of SNC-102 (GastricRetentive Acamprosate formulation) in Acetate Solution (pH 4.5) - (n =6) Mean % Mini- Maxi- of Total 27% * S.D. of % of mum % mum % Time SQRTDrug SQRT Total Drug Re- Re- (hours) Time Released Time Released leasedleased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 24.09 27.00 1.40 23 27 21.4142 36.09 38.18 2.34 34 40 4 2.0000 54.39 54.00 4.02 49 60 6 2.449570.11 66.14 4.15 64 76 10 3.1623 87.67 85.38 4.21 83 95 12 3.4641 92.3193.53 4.38 87 99

TABLE 7 Release of Acamprosate from 400 mg Tablets of SNC-102 (GastricRetentive Acamprosate formulation) in 0.1N HCl (pH 1.0) - (n = 6) Mean %Mini- Maxi- of Total 27% * S.D. of % of mum % mum % Time SQRT Drug SQRTTotal Drug Re- Re- (hours) Time Released Time Released leased leased 00.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 27.00 1.58 24 27 2 1.4142 44.8338.18 3.20 36 41 4 2.0000 63.20 54.00 4.42 56 62 6 2.4495 75.27 66.145.42 69 74 10 3.1623 91.31 85.38 3.59 85 91 12 3.4641 95.99 93.53 2.9690 96

TABLE 8 Release of Acamprosate from 800 mg Tablets of SNC-102 (GastricRetentive Acamprosate formulation) in Acetate Solution (pH 4.5) - (n =6) Mean % Mini- Maxi- of Total 30% * S.D. of % of mum % mum % Time SQRTDrug SQRT Total Drug Re- Re- (hours) Time Released Time Released leasedleased 0 0.0000 0.00 0.00 0.00 0 0 1 1.0000 31.60 30.00 1.58 29 34 21.4142 44.83 42.43 3.20 42 51 4 2.0000 63.20 60.00 4.42 58 64 6 2.449575.27 73.48 5.42 70 84 10 3.1623 91.31 94.87 3.59 87 97 12 3.4641 95.99100.00 2.96 91 100

TABLE 9 Release of Acamprosate from 800 mg Tablets of SNC-102 (GastricRetentive Acamprosate formulation) in 0.1N HCl (pH 1.0) - (n = 6) Mean %Mini- Maxi- of Total 29% * S.D. of % of mum % mum % Time SQRT Drug SQRTTotal Drug Re- Re- (hours) Time Released Time Released leased leased 00.0000 0.00 0.00 0.00 0 0 1 1.0000 28.11 29.00 1.21 26 29 2 1.4142 41.5641.01 1.77 40 44 4 2.0000 61.48 58.00 2.38 57 63 6 2.4495 75.41 71.041.61 73 77 10 3.1623 92.24 91.71 0.55 92 93 12 3.4641 96.62 100.00 0.6596 97

Example 7 Combination of Reformulated Acamprosate with First-GenerationNeuroleptics

First-generation neuroleptic (antipsychotic drugs) have been used forover 50 years in the treatment of schizophrenia and other psychoticdisorders, as well as in the treatment and prevention of nausea andvomiting. The first of these drugs to be introduced to the market waschlorpromazine; others include thioridazine, perphenazine,trifluoperazine, haloperidol, fluphenazine, loxapine, and molindone.Their common feature is that they are all dopamine antagonists at bothD2 and D3 dopamine receptors; each has its own distinctive set ofeffects on receptors for other neurotransmitters. One of the majordrawbacks of these drugs is their propensity to cause movementdisorders. With acute administration that can cause movement disordersincluding parkinsonism (tremor, rigidity, bradykinesia and gaitinstability) as well as dystonia, dyskinesia, and akathisia. Givenchronically they can cause chronic movement disorders that persist evenif the drug is stopped and may even be permanent. These disordersinclude tardive dyskinesia (TD), tardive dystonia, and tardiveakathisia. The incidence of TD and other tardive movement disorders withlong-term use of first-generation neuroleptics exceeds 25%, with an evenhigher rate in elderly patients. In part because of the very high riskof TD, a second generation of neuroleptics was developed that has alower risk of causing TD and related movement disorders with chronicadministration. These drugs include risperidone, quetiapine, clozapine,olanzapine, and aripiprazole. The incidence of TD with these drugs isless than 5%, but all are associated with metabolic side effects ofsufficient severity to affect life expectancy. These side effectsinclude weight gain, glucose intolerance, and disturbances in lipidmetabolism. With the exception of clozapine the second-generationneuroleptics are not more effective in treating schizophrenia and otherpsychotic disorders. Clozapine, while more effective as treatment forsevere mental illness, has additional serious medical side effectsincluding a significant incidence of agranulocytosis that requiresfrequent monitoring of patients' white blood counts as a requirement forusing the drug. The first generation neuroleptics, especially thehigher-potency ones, have a much lower incidence of metabolic sideeffects than the second-generation neuroleptics, and some firstgeneration neuroleptics, e.g., molindone, do not have them at all.

If first generation neuroleptics could be given without a high risk ofcausing or exacerbating tardive dyskinesia they would be preferable tosecond-generation neuroleptics for treating most patients with psychoticdisorders as they would lack the troublesome metabolic side effects ofthe latter. Some embodiments herein relate to utilizing fixed-dosecombinations of first-generation neuroleptics with new formulations ofacamprosate designed for delayed release via a GR delivery system. Suchcombinations would not have been practical heretofore because of thehigh doses of acamprosate needed to treat TD if the existingenteric-coated tablet formulation is used. Given the compliance issuescommon among psychiatric patients a regimen of more than two pills dailywould risk diminished effectiveness. If significantly more than a gramof acamprosate were needed to treat TD the combination of an effectivedose of acamprosate for TD with an effective dose of a first-generationneuroleptic would need to be divided among at least three pills, as adose of enteric-coated acamprosate significantly larger than 500 mg in asingle pill might require that pill to be unpleasantly large, evenwithout the addition of a second drug. The actual dosage ofenteric-coated acamprosate needed to treat TD might in fact be muchhigher—more than 3 grams in some cases. On the other hand, if the neededdose of different formulation of acamprosate needed were less than onegram, treatment effective for both psychosis and TD could be deliveredby one or two combination pills. Such is the case with the instantformulations described herein that provide for sub gram dosages andformulations of acamprosate.

While it is not the case that drugs that prevent a disorder will treatthat disorder, it can be expected that that an effective treatment willattenuate the severity of the disorder, if it does not prevent itcompletely. In the two case examples, patients with established TD and amental disorder took acamprosate together with a neuroleptic and hadcomplete relief of their TD symptoms. Those patients would also be freeof TD symptoms if they took the same combination without having TD atbaseline. The incidence of TD will be lower if a first generationneuroleptic is co-administered with a dose of acamprosate that would beefficacious to treat established TD in the majority of patients. If TDdid develop in some patients the severity would necessarily be less thanif acamprosate were not given.

Some embodiments therefore relate to among other things the followingtwo technologies: (1) Compositions containing a dose of a firstgeneration neuroleptic adequate to treat a psychotic disorder and a doseof acamprosate adequate to treat tardive dyskinesia, includingcompositions in which the doses of the neuroleptic and the acamprosateare combined in a single pill, and compositions in which the doses aredivided into multiple units delivered concurrently, e.g., one tablet ofeach drug in a single blister pack; and (2) The use of such compositionsto treat one or more of schizophrenia, bipolar disorder, schizoaffectivedisorder, depression with psychotic features, delusional disorder, otherpsychotic conditions, the symptoms of hallucinations and delusions. Thecompositions in some aspects further can treat or prevent the symptomsof nausea and vomiting that often accompany the use of such medications.In the described technologies the use may be in patients with or withoutestablished TD.

It is surprising and unexpected that in some embodiments doses ofacamprosate lower than the heretofore-described dosing range fortreating TD can be effectively used, even though such lower doses maynot have the same PK profiles as the enteric-coated pills utilized inpreviously-described treatment of TD—and such lower doses can in someembodiments produce a 24-hour AUC lower than that produced by similarlyefficacious doses of enteric-coated acamprosate. Further, we note theunexpected finding that patients with TD and mental disorders whoreceived acamprosate together with a neuroleptic showed an unexpectedimprovement in anxiety and agitation, even though acamprosate alone doesnot affect these symptoms.

It should be evident that the specific technology for formulating the GRdelivery system for acamprosate does not matter; any system that canmaintain an nearly constant level of acamprosate in the blood for fourhours or more can be used.

Table 8 lists first-generation neuroleptic drugs and range of dailydosages at which they are usually prescribed. Some embodiments hereinrelate to tablets or capsules that implement one of the GR technologiesin Table 9 delivering a dosage of acamprosate between 50 and 500 mg,together with a dose of one of the drugs described in Table 8 at one ofthe dosages specified in that table or a dosage of one-half of theminimum dose in the table below, and up to the maximum dose or any valuethere between. As an example, a tablet might comprise 4 mg ofperphenazine together with 250 mg of acamprosate formulated in aswellable tablet, with the perphenazine surrounding a core ofacamprosate.

TABLE 10 FIRST GENERATION NEUROLEPTICS AND METOCLOPRAMIDE: DAILY DOSAGESAND DOSES FOR FIXED-DOSE COMBINATION PILLS. Example Single Pill Dosagesin Combination with Drug Daily Dose Range Acamprosate Thioridazine10-200 10, 25, 50, 100 Chlorpromazine 25-200 25, 50, 100 Thiothixene2-50 2, 5, 10, 25 Trifluoperazine 5-50 5, 10, 25 Fluphenazine 2-50 2, 5,10, 25 Haloperidol 0.5-50   0.5, 1, 2, 5, 10, 20 Perphenazine 2-32 2, 4,8, 16 Loxapine 10-100 1, 10, 25, 50 Molindone 10-200 10, 25, 50, 100Metoclopramide 5-60 5, 10, 15

Example 8 Combination of Acamprosate with Second-Generation Neuroleptics

The dose of GR acamprosate can be between 100 mg and 800 mg. Theprinciple is that the minimum dose is approximately one-half of thesmallest currently-marketed dose of the drug. Examples of the dosageranges of some non-limiting examples of first-generation neurolepticsare given in Table 10. Examples of dosage ranges for somesecond-generation neuroleptics are shown in the following Table 11. Forexample, the dosage for the neuroleptic can range from one-half of theminimum dose in the table below, and up to the maximum dose, or anyvalue there between:

TABLE 11 Neuroleptic Minimum Dose Maximum Dose aripiprazole 1 mg 30 mgasenapine 1 mg 10 mg iloperidone 1 mg 24 mg lurasidone 10 mg  120 mg olanzapine 1 mg 20 mg paliperidone 1 mg 12 mg quetiapine 12.5 mg   400mg  risperidone 0.25 mg    4 mg ziprasidone 10 mg  80 mg

Example 9 Combination of Acamprosate with SSRI and SSRI Antidepressants

SSRIs and SNRIs are efficacious in OCD and PTSD, both conditions thatalso can respond to treatment with acamprosate. Also, SSRIs and SNRIsare used to treat depressive and anxiety disorders in which recurrent,unwanted, stereotyped thoughts, perceptions, and behavior may be part ofthe syndrome. Since acamprosate and the serotonin reuptake inhibitorshave different mechanisms of action, their therapeutic effects on thesedisorders can be synergistic. The fact that GR acamprosate can beefficacious at a daily dose of less than one gram a day, on a once ortwice daily schedule, makes fixed-dose combinations of GR acamprosatewith an SSRI or SNRI feasible.

The dose of GR acamprosate can be between 100 mg and 800 mg. Someembodiments relate to combinations where the minimum dose isapproximately one-half of the smallest currently-marketed dose of thedrug, for example one-half of the minimum dose in the table below, andup to the maximum dose or any value there between.

TABLE 12 SSRI or SNRI Minimum Dose Maximum Dose Citalopram   5 mg 40 mgDesvenlafaxine   25 mg 100 mg  Duloxetine   5 mg 60 mg Escitalopram  2.5mg 20 mg Fluoxetine   5 mg 40 mg Fluvoxamine 12.5 mg 100 mg  Milnacipran6.25 100 mg  Paroxetine   5 mg 40 mg Sertraline 12.5 mg 200 mg Venlafaxine 12.5 mg 150 mg 

Example 10 Therapeutic Threshold

As noted herein, some embodiments relate to the novel and unexpecteddiscovery that daily dosages of less than 1 gram of acamprosate can beformulated to effectively treat various conditions and disorders. Inparticular, some embodiments relate to formulations and dosage schedulesthat maintain the acamprosate concentration or blood level above athreshold for a sufficient time during each 24-hour period. Suchformulations and schedules can be efficacious even though theacamprosate concentration does not exceed the threshold for the entire24 hour period or even though the concentration or levels of acamprosateare very inconsistent (not at steady levels) during a given period oftime such as a 24 hour period.

According to some embodiments, there are at least a number of parametersthat can be adjusted to optimize clinical effectiveness while stillkeeping the total daily dose of GR acamprosate under 1 gram and limitingtreatment to one or two pills daily: once or twice a day dosage;controlled release time (from 4 to 8 hours or any value between);retention time in the stomach; and dose of acamprosate (from 100 mg to1000 mg). Those parameters are not meant to be limiting.

The following helps illustrate the concept. In a 2010 study, healthyvolunteers were given 666 mg three times daily of enteric coatedacamprosate tablets (Hammarberg et al.: Acamprosate Determinations inPlasma and Cerebrospinal Fluid After Multiple Dosing Measured by LiquidChromatography—Mass Spectroscopy: A Pharmacokinetic Study in HealthyVolunteers. Ther Drug Monit 2010; 32:489-496). It took six days forsteady state blood levels to be attained, after which the average levelfluctuated between 760 ng/mL and 915 ng/mL. By contrast, after a singledose of 666 mg, the C_(max) averaged 286 ng/mL. The authors note thatthe concentrations they observed were higher than those reported byother authors, citing for example a study of alcoholic patients who hada mean steady state concentration of 380 ng/mL on the 666 mg three timesdaily of the enteric coated formulation. It is likely given the efficacyof the 666 mg tid dose in the majority of patients, that the thresholdsteady state level for therapeutic efficacy in alcoholism is less than500 ng/mL.

The threshold blood level for therapeutic efficacy in tardive dyskinesia(TD) and other neuropsychiatric disorders is generally believed to be nohigher than 1000 ng/mL and generally not less than 300 ng/mL, as thedoses used in the successful treatment of TD by the inventor have beenbetween 2 and 4 grams daily.

In the dog study described herein, the subject animals typicallyweighing around 10 kg received a simulated GR dose of 324 mg withrelease proportional to the square root of time over 8 hours—100% of thedrug delivered 7.5 hours after the start of the experiment. In thisstudy the average time the concentration was above 2000 ng/mL after 8.3hours. In view of the—(1) linearity of pharmacokinetics; (2) validity ofextrapolating dosage on a mg/kg basis; (3) validity of simulated GR as apredictor of the function of an actual GR formulation; and (4) humansweighing 70 kg—the concentration of acamprosate above a therapeuticthreshold of 500 ng/mL could be attained for 8 hours with a dose of GRacamprosate of (7*324)/4=567 mg.

While there can be inter-individual variability in body weight and theprecise pharmacokinetic profile, a blood level above a therapeuticthreshold for a human neuropsychiatric disorder can be maintained foreight hours after a single dose of GR acamprosate of less than one gram.

Thus, in some embodiments, a threshold value can an amount of a 300ng/mL to 1000 ng/mL (or any amount of sub range there between) over a4-8 hour period, preferable for about 5-7 hours, more preferably for aperiod of about 6 hours. For example, the threshold value that theacamprosate formulation can meet can be about 500-600 ng/mL for about 6hours.

Some embodiments relate to acamprosate formulations and uses of the samewhere several hours of exposure—typically between 4 and 8 hours—to anadequate level of acamprosate can produce therapeutic effects on CNSfunction lasting for hours after the level of acamprosate falls—andoften for the remainder of a 24 hour day. Thus, a single dose of GRacamprosate pill designed to release the drug over a 4-8 hour period canbe sufficient to give a 24 hour therapeutic effect. Controlled releasetechnology also can be utilized to ensure that a sufficient amount ofacamprosate is released and available during a given time so as to keepthe amount, concentration or level of acamprosate in the patient abovethe threshold.

Gastric retention in the fed state typically lasts about 4 hours. Thus,at the lower end of the controlled release interval of some embodimentsof the technology (4 hours), the controlled release can take placealmost entirely within the stomach. At the upper end of the interval therelease can take place partly in the duodenum and possibly the upperjejunum. This may entail a partial loss of bioavailability, but only forthe quantity of drug not yet released after 4 or more hours, it willapply to less than 50% of the total dose.

Those skilled in the art having the benefit of this application willappreciate that for treating a specific neuropsychiatric condition, theclinical response of a population can be optimized by selecting twice aday rather than once a day dosage, or by reducing the release time from8 hours to 6 hours or 4 hours, for example. When a shorter exposure tothe therapeutic level of acamprosate suffices for persistent efficacy,individual doses can be smaller, or, alternatively, the same dose cansuffice for treating a condition that might otherwise require a higherdose if the release were over 8 hours, for example.

To attain the benefits of the GR formulation of acamprosate described insome of the present embodiments, the specific formulation preferably canrelease 90% or more of the acamprosate within 8 hours. On the otherhand, at least 50% of the acamprosate is released within 3-4 hours, thetypical time the pill (or other dosage form) will remain in the stomachif it is administered in the fed state. The latter criterion ensuresthat the GR preparation will be more bioavailable than enteric-coatedacamprosate, and that it will approach the increased bioavailabilityseen with immediate-release acamprosate delivered directly to thestomach.

One of skill in the art also can titrate dosing to achieve a maintenanceabove a therapeutic threshold for a given patient. For example, aphysician can titrate the dosage upward until a concentration greaterthan 50% of C_(max) for 4-8 hours, preferably about 6 hours.

The fact that therapeutic efficacy can be achieved using acamprosateformulations of less than 1 gram daily with once or twice dailyadministration is surprising and unexpected. That is particularly truewhere the pK curve caused by the formulation maintains a steadyconcentration for only part of (generally for only 4-8 hours) a 24 hourperiod.

Example 11 Induction of Fed Mode Using Alpha-Lipoic Acid

In this example, alpha-lipoic acid is incorporated into a tablet for thepurpose of increasing gastric retention time.

In a dog model, 125 mg of alpha-lipoic acid is administered 15 minutesbefore administration of swellable tablets containing acamprosate andlabeled with barium sulfate. The treatment is performed largely asdescribed in U.S. Pat. No. 7,405,238, the content of which isincorporated herein by reference in its entirety. The retention in thestomach of an 800 mg swellable tablet of maximum dimension 19.05 mm infour beagle dogs (weight 6 kg to 10 kg) is compared with the retentionof such a tablet in either the fasting state or after a 50 gram meal.The results of the test with alpha-lipoic acid are summarized in thefollowing table:

TABLE 13 Minimum gastric Average gastric Maximum retention timeretention time gastric retention Condition (hours) (hours) time (hours)Fasting 0.5 0.9 1.7 After 125 mg 1.5 2.8 5 alpha-lipoic acid After 50 gmeal 3 4.1 4.5

The data from this small sample of dogs support the notion thatalpha-lipoic acid can significantly influence gastric retention time ofan acamprosate-containing tablet, at dosages of alpha-lipoic acid thatare small enough to be practicably incorporated into a tablet forconsumption by a human patient, or to be incorporated into a coating forsuch a tablet.

Example 12 Human Administration of Acamprosate and Alpha-Lipoic Acid

In this example, alpha-lipoic acid is utilized as an immediate-releasecoating of a gastric-retentive tablet containing acamprosate as itsactive pharmaceutical ingredient.

A patient suffering from TD receives an effective but inconvenienttreatment regimen of 3330 mg acamprosate daily, in the form of 10enteric-coated tablets divided into three doses taken without food. Thisregimen is replaced by one of two tablets taken each morning onawakening or alternatively at bedtime, in either case on an emptystomach, each comprising 350 mg acamprosate in a GR formulation coatedwith 150 mg of an immediate-release formulation of R alpha-lipoic acid(it should be understood that the use of “R” alpha lipoic is not to belimiting; racemic alpha lipoic acid can also be used or any other formof the alpha lipoic acid as well). Almost all of the R alpha-lipoic acidpasses through the duodenum before most of the acamprosate reaches theduodenum. The patient experiences adequate relief of TD symptomscompared to his normal regimen of enteric coated acamprosate (i.e.,without gastric retentive formulation), and greatly improved convenienceand treatment regimen adherence.

Example 13 In Vitro Demonstration of Persistent Effect of AcamprosateExposure on Neuronal Response to Glutamatergic Stimulation

The study is designed to test whether pre-treatment with acamprosate canhave long-term neuronal protective effects against glutamateneurotoxicity. The study uses an in vitro organotypic hippocampal slicemodel. The study assesses whether less than 24 hours per day of exposureto a sufficient level of acamprosate can offer 24-hour therapeuticactions in neuropsychiatric disorders. The study demonstrates thepersistent effect of exposure to acamprosate in protecting cultured rathippocampus neurons from challenge with a toxic level of a glutamateagonist drug. This supports, among other things, the therapeutic use ofacamprosate in neuropsychiatric disorders because the latter are relatedto the effect of acamprosate to decrease glutamate effects at NMDA andmetabotropic glutamate receptors. The rat study shows that acamprosatehas a persistent effect on some of the post-synaptic effects ofglutamate agonists even after acamprosate has been removed from theculture medium for up to eight hours.

Hippocampal slices derived from 8-day-old Sprague Dawley rats are platedand subsequently exposed to a relatively acute (8 hour) or more chronic(5 day) acamprosate treatment. The slices are then removed from themedium containing acamprosate and returned to control medium for either1 or 8 hours. The slices will then be challenged with either NMDA (50uM) or a selective mGLuR1 or mGluR5 agent for 1 hr. The slices are thenplaced in normal medium with propidium iodide for 24 hr and assessed forneurotoxicity/neuroprotection as described below.

Methodology:

Preparing an Organotypic Hippocampal Slice Culture (OHSC):

Eight-day old Sprague-Dawley rat pups are used in all organotypichippocampal slice experiments (OHSC) experiments. Pups are sacrificed (3males/3 females per litter) via rapid decapitation, brains are thenaseptically removed and transferred to ice-cold dissecting media.Following removal of the meninges, hippocampi are removed, slicedcoronally at 200 μm and plated in triplicate onto 0.4 μm Bioporemembranes. Membranes are suspended in 1 ml culture media using six-wellplates. Plates are then incubated at 37° C. in a 5% CO₂/21% O₂/74% N₂medical grade gas composition for 5 days in vitro (DIV) to allowaffixture to the Teflon® membrane. Typically, 14-18 slices can bederived from each pup.

Acamprosate Pretreatment:

On the fifth day in vitro the plates are treated with new culturemedium, with half exposed to 200 μM calcium acamprosate and half tonormal medium for either 8 hr or 5 days. At this time, the plates areplaced into fresh control medium for either 1 hr or 8 hr.

Glutamatergic Challenge:

At this time, the plates are placed either in fresh medium, medium withNMDA (50 uM) or a metabotropic glutamate receptor agonist for 1 hour.

Neurotoxicity/Neuroprotection Assessment:

For the final medium change, the plates are moved into normal mediacontaining propidium iodide (PI) added to each well for 24 hours. PIonly penetrates cell membranes of damaged or potentially dying cells,binding to DNA to produce a bright, intensified red fluorescence at 630nm. The slices are visualized with SPOT Advanced version 4.0.2 softwarefor Windows at a 5× objective with a Leica DMIRB microscope that isfitted for fluorescent detection using blue-green light, and connectedto a personal computer through a SPOT 7.2 color mosaic. The emissionwavelength of PI is 620 nm in the visual range; PI has a peak excitationwavelength of 536 nm. PI is excited using a band-pass filter excitingwavelengths between 510 and 560 nm. Intensity of the PI fluorescence isanalyzed by densitometry using Image J and the pictures are quantifiedby detecting optical intensity of the CA1 pyramidal cell layer, CA3pyramidal cell layer, and dentate gyrus granule cell layer of thehippocampus following background subtraction. Fluorescence is recordedin arbitrary units, then converted to percent of control, facilitatingcomparison across multiple cultures and controlling for variationbetween litters. PI uptake has been shown to correlate well with othermeasures of cellular injury and cellular death.

Example 14

Acamprosate is tested using a rat model of tardive dyskinesia looking atabnormal chewing movements produced in rats by exposing them for severalweeks to haloperidol, a potent first-generation neuroleptic. First,acamprosate is tested and shows a steadily-maintained blood level willreduce or eliminate the abnormal movements. Rats then are dosed withacamprosate in a way that matches the therapeutic blood level for nomore than 12 hours out of 24, to confirm that this reduces theinvoluntary movements.

Example 15

Acamprosate is tested in transgenic mouse models with movement disorders[(Per2(Brdm1) deletion or ENT1(−/−) mice or other mouse models] andhyperglutamatergic states. First, acamprosate is tested and shows asteadily-maintained blood level will reduce or eliminate the abnormalmovements. Mice then are dosed with acamprosate in a way that matchesthe therapeutic blood level for no more than 12 hours out of 24, toconfirm that this reduces the involuntary movements.

Example 16

The pharmacokinetic properties of the specific gastric-retentive (GR)preparation of acamprosate described in EXAMPLE 5 is tested in humansubjects in two studies. In the first, subjects receive, 30 minutesafter a standard high-fat meal, a single dose of 400 mg of GRacamprosate, of 800 mg of GR acamprosate, or of 666 mg of enteric-coatedacamprosate. Plasma concentrations of acamprosate are determined at 1,2, 4, 6, 8, 12, 24, and 48 hours afterwards and pharmacokineticparameters are calculated.

In at least some subjects (a) C_(max) and AUC are proportional to dosagefor the 400 and 800 mg GR dosages, and (b) with respect to the 666enteric-coated dosage, the GR formulations have higher bioavailabilityand a shorter T_(max).

In the second study subjects receive 400 mg of GR acamprosate in thefasting state, in the fed state, and in the fasting state preceded(e.g., at least 10-15 minutes earlier) by 600 mg of R alpha lipoic acid.

In at least some subjects the pharmacokinetic curve (and the parametersAUC, C_(max) and T_(max)) are similar for 400 mg of GR acamprosate inthe fed state and for 400 of GR acamprosate in the fasting statepreceded by R alpha lipoic acid; 400 mg of GR acamprosate in the fastingstate without alpha lipoic acid shows a significantly lower AUC andlower C_(max) than either of the other two conditions.

The herein described subject matter sometimes illustrates differentmethods, compositions and/or components contained within, or combinedwith, different other methods, compositions and/or components. It is tobe understood that the various described methods, compositions,components and combinations of the same are merely provided asnon-limiting examples, and that in fact many others can be implementedwhich achieve the same purposes and/or functionality.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the embodiments of the technology.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present embodimentsare not entitled to antedate such publication by virtue of priorinvention. Further, the dates of publication provided may be differentfrom the actual publication dates which may need to be independentlyconfirmed. The subject matter disclosed in the publications, includingany methods, compositions, excipients (including ranges and dosages ofthe same), etc., are incorporated herein by reference in theirentireties.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. Also, while various aspects and embodiments havebeen disclosed herein, other aspects and embodiments will be apparent tothose skilled in the art. The various aspects and embodiments disclosedherein are for purposes of illustration and are not intended to belimiting, with the true scope and spirit being indicated by thefollowing claims.

What is claimed is:
 1. A tablet comprising: 800 mg of acamprosatecalcium or other pharmaceutically acceptable salt of acamprosate,distributed within a polymer matrix that comprises or consists of 60 mgof carbomer homopolymer type B.
 2. The tablet of claim 1, wherein thetablet is small enough to be easily swallowed.
 3. The tablet of claim 2,wherein the tablet is spheroid shaped.
 4. The tablet of claim 2, whereinthe tablet further comprises a neuroleptic or metoclopramide.
 5. Thetablet of claim 4, wherein the neuroleptic is selected from the groupconsisting of aripiprazole, asenapine, chlorpromazine, fluphenazine,haloperidol, iloperidone, loxapine, lurasidone, molindone, olanzapine,paliperidone, perphenazine, quetiapine, risperidone, thioridazine,thiothixene, trifluoperazine, and ziprasidone.
 6. The tablet of claim 4,wherein the tablet further comprises metoclopramide.
 7. The tablet ofclaim 5, wherein the neuroleptic is molindone.
 8. the tablet of claim 5,wherein the neuroleptic is quetiapine.
 9. The tablet of claim 5, whereinthe neuroleptic is aripiprazole.